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Cellular Pathways of Hereditary Spastic Paraplegia∗

Craig Blackstone

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA; email: [email protected]

Annu. Rev. Neurosci. 2012. 35:25–47 Keywords First published online as a Review in Advance on spasticity, lipid droplet, BMP, cytokinesis, , endoplasmic April 20, 2012 reticulum

Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org The Annual Review of Neuroscience is online at by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. neuro.annualreviews.org Abstract This article’s doi: Human voluntary movement is controlled by the pyramidal motor 10.1146/annurev-neuro-062111-150400 system, a long CNS pathway comprising corticospinal and lower mo- ∗ This is a work of the U.S. Government and is not tor . Hereditary spastic paraplegias (HSPs) are a large, geneti- subject to copyright protection in the United States. cally diverse group of inherited neurologic disorders characterized by a length-dependent distal axonopathy of the corticospinal tracts, resulting in lower limb spasticity and weakness. A range of studies are converging on alterations in the shaping of , particularly the endoplasmic reticulum, as well as intracellular membrane trafficking and distribution as primary defects underlying the HSPs, with clear relevance for other long axonopathies affecting peripheral nerves and lower motor neurons.

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in the body; their extend up to 1 m in > Contents length and the comprises 99% of total cell volume. This length has evolved to INTRODUCTION...... 26 permit the very rapid relay of action potentials, COMMON CELLULAR enabling timely voluntary movement, but it PATHOGENIC THEMES...... 28 comes at great expense to the : Complex AxonPathfinding...... 28 intracellular machineries are required for sort- Myelination...... 28 ing and distributing , lipids, mRNAs, Endoplasmic Reticulum organelles, and other molecules over such Network Morphology ...... 31 long distances. These machineries utilize an Lipid Synthesis and Metabolism . . . . 34 elaborate neuronal cytoskeletal scaffold along EndosomalDynamics...... 35 which motor proteins target and deliver com- Motor-BasedTransport...... 37 ponents selectively throughout the cell; axonal Mitochondrial Function ...... 37 transport machineries rely on RELATEDDISORDERS...... 37 in particular, which function as polarized EPLURIBUSUNUM?...... 38 tracks with their plus ends oriented toward the Bone Morphogenetic terminal. A variety of mechanoenzymes ProteinSignaling...... 38 within the kinesin, dynein, and myosin Interorganelle Contacts superfamilies mediate much of the anterograde andCommunication...... 39 and retrograde transport specificity through CONCLUDINGREMARKS...... 39 selective cargo interactions. Additional speci- ficity and regulatory control are contributed by various adaptor proteins. The interaction of intracellular cargoes with these complexes per- INTRODUCTION mits tightly regulated, selective allocations of Voluntary movement in humans relies on the organelles, proteins, lipids, and other molecules pyramidal motor system, a tortuous, multisy- to growth cones during axonal development naptic pathway in the CNS that extends from and to specialized axon domains such as branch the cerebral motor cortex to neuromuscular points, internodal segments, and presynaptic junctions innervating . This sys- terminals in mature neurons (Goldstein et al. tem is arranged in two main stages (Figure 1). 2008, Arnold 2009, Hirokawa et al. 2010). First, axons of large pyramidal neurons origi- Not surprisingly, long axons are an Achilles’ nating in layer V of the cerebral motor cortex heel of the ; length-dependent course through the medullary pyramids, where defects in axon development and maintenance most fibers decussate in the caudal medulla be- give rise to a host of neurological disorders, Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. fore descending as lateral corticospinal tracts both acquired and inherited. Acquired disor- within the spinal cord. Although some corti- ders are numerous and highly varied, with eti- cospinal axons establish directly with ologies encompassing injuries, nutritional defi- lower motor neurons in the spinal cord ante- ciencies, endocrine and metabolic disturbances, rior horn, the vast majority with spinal infections, and environmental toxins, to name , which then establish connections a few; these are not discussed here. The focus with lower motor neurons. In the next stage, of this review is on inherited Mendelian dis- lower motor neurons terminate in specialized orders, as exemplified by the hereditary spastic synapses at neuromuscular junctions through- paraplegias (HSPs). Although these are among out the body to regulate skeletal muscle con- the most genetically diverse of all diseases, with HSP: hereditary tractility (Figure 1) (Carpenter 1991). nearly 50 distinct loci and more than 20 spastic paraplegia Distances traversed by corticospinal and products identified to date, they are unified by lower motor neurons are among the furthest the defining, predominant clinical feature of

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progressive lower limb spasticity and weakness, with sparing of the upper limbs to a large extent Upper (Fink 2006, Depienne et al. 2007, Salinas et al. cell body 2008, Dion et al. 2009, Blackstone et al. 2011, Lang et al. 2011). HSPs are uncommon but not rare, with a prevalence of ∼3–9/100,000 in most popula- tions, and thus likely afflict several hundred thousand individuals worldwide. Inheritance can be X-linked recessive, autosomal recessive, or autosomal dominant, and age at onset can vary widely, from early childhood to late in life. HSPs have historically been classified as pure or complicated on the basis of the absence (pure) or presence (complicated) of associated clinical features such as distal amyotrophy, Corticospinal cognitive dysfunction, retinopathy, ataxia, thin axon corpus callosum, and peripheral neuropathy (Harding 1983). Even in pure forms, urinary Midbrain symptoms and mild dorsal column sensory deficits are frequently encountered. More recently, a numeric labeling scheme has taken hold, and HSPs are increasingly referred to mainly by their genetic classification, SPG1-48 Pons (Depienne et al. 2007, Salinas et al. 2008, Dion et al. 2009, Blackstone et al. 2011). Because most patients with HSP have a normal life span, a limited number of neu- ropathologic evaluations of HSPs have been Caudal Decussation of pyramids published, particularly for the most instructive medulla pure forms with a genetic diagnosis. Still, these studies have typically shown evidence of axonal degeneration, principally involving the longest ascending sensory fibers and descending cor- Lumbar spinal cord ticospinal tract axons in a distal, “dying-back” Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. manner (DeLuca et al. 2004). Because the longest corticospinal axons control the lower motor neurons innervating muscles of the lower limbs, such findings are concordant with Skeletal the cardinal clinical features of HSP; sensory muscle manifestations tend to be clinically mild. There is usually little neuronal death even late in the disease course, especially in pure forms, so HSPs are a prototype for understanding disorders that impair axons (Soderblom & Figure 1 Blackstone 2006). Importantly, HSPs are fun- Schematic diagram of the corticospinal tract emphasizing its descent through the CNS. Although most fibers decussate in the caudal medulla, a minority of damentally diseases of massive scale, affecting fibers descend uncrossed as the ventral corticospinal tract (not shown).

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predominantly the longest neurons that are or- mic tail. L1CAM participates in a complex set ders of magnitude larger than most other cells. of extracellular and intracellular interactions, binding not only other L1CAM molecules but Spasticity: increase in muscle tone associated COMMON CELLULAR also a host of extracellular ligands—including with hyperactive PATHOGENIC THEMES other cell adhesion molecules, integrins, and tendon stretch reflexes proteoglycans—as well as intracellular proteins The common clinical and pathological features such as ankyrins. Disease mutations are found Corpus callosum: of different HSPs prefigure a small number of arched bridge of nerve throughout the protein, and partial or complete common themes at the cellular level, and the fibers connecting the loss of L1CAM function seems critical for the genetic heterogeneity provides a significant left and right cerebral L1 disease phenotype. In L1CAM null mice, the hemispheres advantage in identifying these convergent corticospinal tracts are abnormal, arising from themes. Indeed, published studies have indi- a conspicuous failure to decussate within the cated that HSP disease proteins cluster within medulla (Dahme et al. 1997, Cohen et al. 1998). a small number of predicted cellular processes How does this pathfinding defect occur? In (Table 1 and Figure 2) (Soderblom & the developing CNS, L1CAM associates with Blackstone 2006, Depienne et al. 2007, Salinas neuropilin-1 (Nrp1), which itself interacts with et al. 2008, Dion et al. 2009, Blackstone et al. -A proteins to form the Semaphorin3A 2011). Although we discuss HSP proteins by (Sema3A) receptor complex. Upon Sema3A topic, one must remember that many of them binding to Nrp1, L1CAM and Nrp1 are coin- appear to function in a number of different ternalized in a L1CAM-dependent manner. pathways; thus pathogenic groupings may Sema3A is a repulsive guidance cue released evolve over time. from cells in the ventral spinal cord to steer cor- ticospinal neurons away from the midline spinal Axon Pathfinding cord/medullary junction, and L1CAM muta- Among the first HSP mutations described were tions may affect Sema3A signaling when axons in the L1CAM gene, encoding a cell surface gly- are crossing the midline by interfering with re- coprotein of the immunoglobulin (Ig) super- ceptor internalization and signaling at growth family. Loss-of-function mutations in L1CAM cones (Castellani et al. 2004). In fact, the as- are implicated not only in X-linked, early-onset, sociation of Nrp1 with L1CAM mediates the complicated HSP (SPG1), but also in other activation of a focal adhesion kinase-mitogen- X-linked syndromes including MASA (for men- activated protein kinase pathway controlling a tal retardation, aphasia, shuffling gait, and ad- critical aspect of the repulsive behavior, the dis- ducted thumbs), hydrocephalus, and agenesis of assembly of adherent zones in growth cones the corpus callosum ( Jouet et al. 1994, Weller and their subsequent collapse (Bechara et al. &Gartner¨ 2001). Each of these disorders dis- 2008). This compelling role of L1CAM in axon Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. plays clinical and pathological evidence of cor- pathfinding during development is consistent ticospinal tract impairment; the disorders are with the early onset of SPG1. considered together along a disease spectrum known as L1 disease or CRASH syndrome (for corpus callosum hypoplasia, retardation, Myelination adducted thumbs, spastic paraplegia or shuf- A distinguishing feature of axons in the central fling gait, and hydrocephalus) (Soderblom & and peripheral nervous systems is an insulating Blackstone 2006). sheath, a specialization important for The L1CAM protein is more than 1200 increasing the speed of electrical impulse amino acid residues in size, with a large extra- propagation. Schwann cells supply myelin for cellular segment harboring 6 Ig-like domains peripheral neurons, whereas and 5 fibronectin type III domains, a single myelinate axons of CNS neurons. Spastic transmembrane domain, and a short cytoplas- paraplegia as a manifestation of abnormal

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Table 1 Identified HSP , grouped functionallya,b Disease/geneb Protein name Inheritance Cellular functions Membrane traffic and shaping SPG3A/ATL1 Atlastin-1 AD ER morphogenesis BMP signaling SPG4/SPAST Spastin (M1 and M87 isoforms) AD severing ER morphogenesis Endosomal traffic BMP signaling Cytokinesis SPG6/NIPA1 NIPA1 AD Endosomal traffic + Mg2 transport BMP signaling SPG8/KIAA0196 Strumpellin AD Endosomal traffic Cytoskeletal (actin) regulation SPG10/KIF5A KIF5A AD Microtubule-based motor protein SPG11 Spatacsin AR Endosomal traffic SPG12/RTN2 Reticulon 2 AD ER morphogenesis SPG15/ZFYVE26 Spastizin/ AR Endosomal traffic ZFYVE26/ Cytokinesis FYVE-CENT Autophagy SPG17/BSCL2 Seipin/BSCL2 AD Lipid droplet biogenesis at ER SPG18/ERLIN2 Erlin2 AR ER-associated degradation Lipid raft-associated SPG20 Spartin AR Endosomal traffic BMP signaling Cytokinesis Lipid droplet turnover Mitochondrial regulation SPG21 Maspardin AR Endosomal traffic SPG31/REEP1 REEP1 AD ER morphogenesis ER-microtubule interaction SPG48/KIAA0415 KIAA0415 (AP-5 subunit) AR Endocytic adaptor protein complex AP-4 deficiency/AP4S1, AP4B1, AP4E1 AP-4 S1, B1, and E1 subunits AR Endocytic adaptor protein complex JPLS/ALS2 Alsin AR Endosomal traffic Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. Mitochondrial regulation SPG7 Paraplegin AR Mitochondrial m-AAA ATPase SPG13/HSPD1 HSP60 AD Mitochondrial chaperonin Myelination and lipid/sterol modification SPG2/PLP1 Proteolipid protein X-linked Major myelin protein SPG5/CYP7B CYP7B1 AR Cholesterol metabolism SPG35/FA2H Fatty acid 2-hydroxylase AR Myelin lipid hydroxylation SPG39/PNPLA2 Neuropathy target esterase AR Phospholipid homeostasis SPG42/SLC33A1 SLC33A1 AD Acetyl-CoA transporter SPG44/GJC2 Connexin-47 AR Intercellular channel Axon Pathfinding SPG1/L1CAM L1CAM X-linked Cell adhesion and signaling aAbbreviations: AD, autosomal dominant; AR, autosomal recessive; BMP, bone morphogenetic protein; ER, endoplasmic reticulum. bWhen different from disease name. www.annualreviews.org • Hereditary Spastic Paraplegia 29 NE35CH02-Blackstone ARI 14 May 2012 10:46

Myelin/oligodendrocytes (PLP, CX47, FA2H)

Mitochondria Golgi Anterograde transport Microtubules Tubular ER (paraplegin, (SLC33A1) (KIF1A, KIF5A) (spastin, REEP1) (atlastin-1, erlin2, (NIPA1, spastizin, spartin, HSP60, spartin) seipin, spastin, spatacsin, spastin, strumpellin REEP1, reticulon 2) maspardin, AP4, AP5, alsin)

Figure 2 Common pathogenic themes in the HSPs. This schematic representation of a corticospinal motor neuron emphasizes where HSP gene products as listed in Table 1 are proposed to function. L1CAM is an integral membrane protein localized to the plasma membrane. CYP7B1 and NTE distributions are not shown, pending more detailed studies of their sites of action.

myelination in the CNS is not uncommon; for regions (Edgar et al. 2004, Gruenenfelder example, this occurs in multiple sclerosis and a et al. 2011). It seems reasonable to postulate variety of acquired and inherited leukodystro- that oligodendrocytes modulate the activity of phies. Mutations in the PLP1 gene encoding motor proteins involved in intracellular cargo the tetraspan integral membrane proteolipid transport via signaling cascades in the under- protein (PLP) and its smaller DM20 isoform lying axon and that this modulation is sensitive give rise to two major diseases along a clinical to PLP/DM20 (Gruenenfelder et al. 2011). spectrum: a pure or complicated HSP (SPG2) Mutations in a more recently identified and the generally much more severe Pelizaeus- HSP gene similarly define a disease spectrum Merzbacher disease (PMD) (Inoue 2005). comprising HSP and PMD-like disease where Although PLP and DM20 are the major pro- cell-cell communication is altered. The slowly ∼ Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org

by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. tein constituents of CNS myelin ( 50% of the progressive, complicated SPG44 is caused total protein), PLP1 duplications paradoxically by homozygous mutations in the GJC2 gene cause more severe disease than do deletions, encoding connexin 47 (CX47). Connexins (typ- whereas complete absence of PLP/DM20 is ically numbered based on predicted molecular typically associated with SPG2 or mild presen- weight) are oligomeric proteins forming gap tations of PMD. Plp1 null mice in particular junction channels, which establish connections have been widely studied as a model for SPG2. between apposed cell membranes to permit Unexpectedly, in these mice the myelin sheath the intercellular diffusion of ions and small Intraperiod lines: maintains its normal thickness, though with molecules (typically <1000 Da). CX47 forms fused outer leaflets of subtle anomalies of the intraperiod lines. In connections between and oligo- contiguous plasma the underlying axons, anterograde transport is dendrocytes in concert with CX43. Because membranes in the impaired, and cargoes undergoing retrograde CX47/CX43 heterotypic channels appear myelin sheath transport become stuck at distal juxtaparanodal essential for the maintenance of CNS myelin,

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alterations in CX47 that result in CX47/CX43 mitochondrial morphology is shaped by the channel dysfunction likely underlie SPG44 opposing processes of fission and fusion, and (Orthmann-Murphy et al. 2009). multiple large GTPases involved in regulating A third HSP with a compelling link to this balance are mutated in autosomal dominant dysmyelination is autosomal recessive SPG35. neurological disorders, including optic atrophy This disorder sits along a disease spectrum type 1 (OPA1) and Charcot-Marie-Tooth type spanning neurodegeneration with brain iron 2A neuropathy (MFN2) (Westermann 2010). accumulation, leukodystrophy, and HSP and An analogous situation occurs in the en- results from loss-of-function mutations in the doplasmic reticulum (ER), and the roles of fatty acid-2 hydroxylase gene FA2H (Dick et al. common HSP gene products in shaping the 2010, Schneider & Bhatia 2010). The FA2H tubular ER network have indicated this may protein is a nicotinamide adenine dinucleotide be the most common pathogenic theme (Park phosphate (NADPH)–dependent monooxyge- et al. 2010, Montenegro et al. 2012). The ER is nase that converts free fatty acids to 2-hydroxy among the most distinctive organelles because fatty acids. These are incorporated into myelin of its large size, morphological heterogeneity, galactolipids containing hydroxy fatty acid as and extension throughout the cell. Although the N-acyl chain, which maintains the myelin it is a continuous membrane-bound luminal sheath. Fa2h null mice have been developed system, it comprises the distinct morphologies as a model for SPG35, and these animals of the nuclear envelope (with thousands exhibit significant demyelination, axon loss of specialized pores), peripheral sheet-like or enlargement, cerebellar defects, and spatial structures studded with polyribosomes, and a learning and memory deficits. Animals lacking polygonal network of interconnected smooth Fa2h only in oligodendrocytes and Schwann tubules distributed widely throughout the cell. cells do not exhibit memory deficits, indicating Concordant with this structural heterogeneity, that some neurological manifestations may the ER is a multifunctional organelle involved derive from a lack of FA2H in other cell types in the synthesis, modification, quality control, (Potter et al. 2011). and trafficking of integral membrane and Taken together, this subgroup of HSPs secreted proteins. It is critical as well for Ca2+ most exemplifies a noncell-autonomous disease sequestration and release, signaling, sterol syn- pathogenesis. In this regard, oligodendrocytes thesis, and lipid synthesis and distribution. In from Plp1 null mice were able to induce a focal neurons, the ER plays crucial roles in the mas- axonopathy when transplanted into the dorsal sive polarized membrane expansion that occurs columns of the myelin-deficient shiverer mouse during axon and genesis and as an in- (Edgar et al. 2004). Thus, HSP-associated alter- tracellular Ca2+ store integrated with pre- and ations in -mediated myelina- postsynaptic signaling pathways (Verkhratsky Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. tion can directly cause changes in the underly- 2005, Park & Blackstone 2010, Renvoise&´ ing axon, impairing corticospinal tract function. Blackstone 2010, Lynes & Simmen 2011). The three most common autosomal dom- inant HSPs—SPG3A, SPG4, and SPG31—as Endoplasmic Reticulum well as the less common SPG12 result from Network Morphology mutations in proteins directly implicated in the Cellular organelles have diverse but charac- formation of the tubular ER network, which is teristic morphologies that are evolutionarily overwhelmingly smooth ER (Park et al. 2010, conserved, indicating that the function of an Montenegro et al. 2012). Mutations in the organelle is fundamentally related to its form. SPG3A gene ATL1 are the second most com- An obvious corollary is that disruption of form mon cause of HSP and are the most common can give rise to disease, and in fact, this has been cause of early-onset disease. The SPG3A pro- shown for a number of organelles. For instance, tein atlastin-1 is a member of a family of large

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Nuclear envelope Rough ER

Golgi Smooth ER

M1 spastin

AAA REEP 1-4

REEP5-6 Atlastin-1 MIT MTB reticulon GTP Atlastin-1

ER lumen Smooth tubular ER

Figure 3 Spastin, atlastin, REEP, and reticulon proteins interact and shape the endoplasmic reticulum (ER) network. (Left) Schematic diagram of a neuron showing the distribution of different ER domains. Below this schematic is an enlargement of a three-way tubular ER junction. REEP and reticulon proteins form large oligomers to shape the tubular ER. Atlastin proteins are enriched in puncta along the tubules, including at three-way junctions. (Right) Proposed membrane topologies for protein families involved in generating the tubular ER network. GTP, atlastin GTPase domain; MTB, microtubule-binding domain.

oligomeric GTPases related to the dynamin the ER-Golgi intermediate compartment and superfamily. Atlastin-1 is one of three homol- in the cis-Golgi apparatus in some cell types ogous proteins in mammals (atlastin-1, -2 and (Zhu et al. 2003, 2006; Rismanchi et al. 2008). -3) thought to be paralogs, but it is the only Atlastin GTPase activity is required for the form expressed highly in the CNS (Zhu et al. formation of the three-way junctions in ER 2003, Rismanchi et al. 2008). Atlastin-related tubules in a wide range of species by directly GTPases are found in all eukaryotic cells and mediating homotypic fusion of ER tubules include Sey1p in Saccharomyces cerevisiae and (Rismanchi et al. 2008, Hu et al. 2009, Orso Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. root hair defective 3 (RHD3) in Arabidopsis (Hu et al. 2009, Bian et al. 2011, Byrnes & et al. 2009). In contrast with mammals, species Sondermann 2011, Chen et al. 2011, Moss et al. such as S. cerevisiae and Drosophila melanogaster 2011). Consistent with this role, atlastins local- Dynamin have only a single atlastin ortholog. Across ize to discrete sites along ER tubules, including superfamily: large, species, the atlastins can diverge considerably at three-way junctions. Depletion of atlastin-1 multimeric GTPases involved in membrane at the sequence level, but all share a similar by shRNA in cultured cortical neurons inhibits fission or fusion domain organization: a large cytoplasmic axon elongation (Zhu et al. 2006), and there Root hairs: long, N-terminal domain containing a tripartite is a link between proper ER morphology and thin, tubular GTP-binding domain, two very closely spaced the formation and maintenance of long cellular outgrowths of plant hydrophobic segments, and a small cytoplasmic processes such as axons and plant root hairs (see root epidermal cells C-terminal tail (Figure 3). These multimeric, sidebar, ER Shaping: Plant Roots to Axons). that absorb water and integral membrane GTPases localize predom- Mammalian atlastins and yeast Sey1p (syn- minerals from soil inantly to the tubular ER but are also found in thetic enhancement of yop1) interact directly

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with the reticulon and Yop1p/DP1/REEP fam- ilies of ER-shaping proteins in the tubular ER ER SHAPING: PLANT ROOTS TO AXONS (Hu et al. 2009, Park et al. 2010). Members of these families each have two long hydropho- In the flowering plant Arabidopsis, root hairs are long processes bic stretches that form intramembrane hair- emanating from root epidermal cells. Like axon growth, root hair pin domains predicted to partially span the tip growth is an extreme form of polarized cell expansion reg- lipid bilayer, inducing and/or stabilizing high- ulated by signaling molecules, Ca2+ flux, cytoskeletal dynamics, curvature ER tubules via hydrophobic wedging GTPases of the , Arf, and Rho/Rac families, and reactive oxy- (Voeltz et al. 2006, Hu et al. 2008, Shibata et al. gen species. Loss-of-function mutations in the atlastin/SPG3A 2009, West et al. 2011). Mutations in REEP1 ortholog RHD3 have highlighted the importance of proper ER cause an autosomal dominant, pure HSP known morphology in Arabidopsis root hair formation (Wang et al. 1997, as SPG31. REEP1 belongs to a family of re- Chen et al. 2011). rhd3 mutant plants have abnormal tubular ER lated proteins (REEP1–6 in mammals) and was bundles within short, wavy root hairs and an unusually large num- originally identified on the basis of its ability ber of vesicles in subapical (rather than apical) hair regions. This to promote trafficking of olfactory receptors to defective polarized expansion may reflect decreased or misplaced the plasma membrane surface (Saito et al. 2004). deposition of secretory vesicles during root hair elongation. Al- REEP1 localizes to the tubular ER and inter- though ER tubules in plants are oriented mostly along actin acts with atlastin-1 via its predicted hydropho- fibers, root hair tip growth depends on microtubules also, and bic hairpin motifs. Some members (REEP1–4) ER morphology changes during root hair elongation (Sieberer also have an extended C-terminal domain (rel- et al. 2005). Given the speed and adaptability of Arabidopsis ge- ative to REEP5–6) that binds microtubules, es- netics and conservation of atlastin/RHD3 GTPases as well as tablishing REEP1 as a member of a subfamily ER-shaping reticulon/REEP proteins (Sparkes et al. 2011), con- of REEPs (REEP1–4) involved not only in ER tinued studies of root hair elongation will likely provide insights shaping but also in interactions of ER tubules into the functions of ER in axon growth and maintenance. with the microtubule cytoskeleton (Park et al. 2010, Blackstone et al. 2011). Very recently, mutations in the RTN2 gene encoding the ER- further by the fact that the SPG4 protein shaping protein reticulon 2 have been identified spastin, a microtubule-interacting and sever- in families with autosomal dominant SPG12 ing AAA ATPase, binds atlastin-1 and REEP1 (Montenegro et al. 2012). as well as the ER-shaping protein reticulon The fundamental link between the tubular 1 (Evans et al. 2006, Mannan et al. 2006, ER and microtubules has been appreciated for Sanderson et al. 2006, Connell et al. 2009, Park decades (Terasaki et al. 1986), and although et al. 2010). Spastin occurs as two main iso- the microtubule cytoskeleton is not absolutely forms generated by differential use of AUG required for ER network formation (Shibata start codons: a 60-kDa form and a 67-kDa form Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. et al. 2009), microtubule-based ER motility is (Mancuso & Rugarli 2008). The larger iso- key for the proper organization and distribu- form has an additional 86 amino acid stretch tion of ER tubules. This is achieved through at the N-terminus containing a hydrophobic a variety of mechanisms: membrane sliding, in segment predicted to insert in the ER mem- which ER tubules slide along microtubules us- brane as a partially membrane-spanning hair- ing motor activity; microtubule movement, in pin (Park et al. 2010). Interactions of M1 spastin Hydrophobic wedging: partitioning which ER tubules latch on to moving micro- with REEP1 and atlastin-1 appear to be medi- the bulk of tubules; and the tip attachment complex, in ated largely through this hairpin, though flank- intramembrane which ER attaches to growing microtubule plus ing regions may also participate (Evans et al. hydrophobic domains ends (Waterman-Storer & Salmon 1998). 2006, Sanderson et al. 2006). The larger spastin within one leaflet of a Impairment of this relationship between ER isoform is particularly enriched in the spinal phospholipid bilayer, generating membrane tubules and the microtubule cytoskeleton as a cord, and a dysfunctional M1 spastin polypep- curvature pathogenic mechanism for HSPs is supported tide, but not one representing the shorter M87

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form (M85 in rodents), was deleterious to axon been implicated in LD formation (Hapala growth in cultured neurons (Solowska et al. et al. 2011). However, it will be important to 2008), strengthening the evidence linking M1 investigate any effects of misfolded seipin on Lipid droplet (LD): dynamic cytoplasmic spastin to HSP pathogenesis. By comparison, other aspects of ER structure and function. organelle consisting M87 spastin appears involved in cytokinesis, se- Recently, the gene for the complicated, of a phospholipid cretion, and possibly through its autosomal recessive SPG18 was identified in monolayer interactions linking microtubule dynamics to a consanguinous Saudi family as ERLIN2 surrounding a neutral membrane modeling in these compartments (Alazami et al. 2011). A second study inde- lipid core; proteins are found within the (Yang et al. 2008, Connell et al. 2009). In pendently identified loss-of-function ERLIN2 monolayer and sum, there appear to be strong physical and mutations in a family with motor dysfunc- decorating its surface functional links between M1 spastin, atlastin- tion, joint contractures, and intellectual dis- 1, reticulon 2, and REEP1 involved in shaping ability (Yıldırım et al. 2011). The erlin2 pro- the tubular ER network in concert with the mi- tein resides in the ER and contains a SPFH crotubule cytoskeleton. Even so, the ER has a domain—named for its presence in stom- large number of functions, and it remains un- atin, prohibitin, flotillin, and HflC/K. SPHF clear which are most pathogenically relevant for domain–containing proteins share the ability to HSPs. assemble into large oligomers, and they localize Because several other HSP proteins also preferentially to cholesterol-rich domains, in- localize to the ER, understanding these may cluding lipid rafts (Browman et al. 2006). Erlin2 clarify the role of ER in HSP pathogenesis. has been functionally linked to ER-associated Mutations in the Berardinelli-Seip congenital degradation (ERAD), a multistep degradative lipodystrophy protein 2 gene BSCL2, which pathway encompassing ubiquitin-proteosome- encodes an integral membrane of the ER mediated degradation of ER proteins, thereby known as BSCL2/seipin, cause two distinct regulating levels of proteins such as the inosi- diseases. Heterozygous gain-of-function muta- tol trisphosphate receptor (Pearce et al. 2009). tions in an N-linked glycosylation site give rise Also, erlin2 binds gp78, a membrane-bound to a disease spectrum encompassing autosomal ubiquitin ligase similar to HRD1 that medi- dominant SPG17 (Silver syndrome), with distal ates sterol-accelerated ERAD of 3-hydroxy-3- amyotrophy as a significant feature in addition methyl-glutaryl (HMG)-CoA reductase, a key to spastic paraparesis, and distal hereditary enzyme in the biosynthesis of cholesterol ( Jo motor neuropathy type V, characterized by et al. 2011). more prominent distal spinal muscular atrophy (Windpassinger et al. 2004). In contrast, auto- somal recessive loss-of-function mutations give Lipid Synthesis and Metabolism rise to Berardinelli-Seip congenital lipodys- These latter two HSP proteins, erlin2 and Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. trophy, without spasticity or amyotrophy. The seipin, present compelling insights into how seipin protein and its yeast ortholog, Fld1p defects in ER shaping and distribution might (few lipid droplets 1), regulate the size of lipid cause HSP. A key function of the ER is the droplets (LDs), explaining the loss-of-function synthesis, metabolism, and distribution of lipodystrophy presentation (Cui et al. 2011; Fei lipids and sterols, employing both vesicular et al. 2011a,b; Tian et al. 2011). The missense and nonvesicular mechanisms, and other changes underlying SPG17 have resulted in HSP proteins fit into this pathogenic theme. misfolding of seipin, forming aggregates and The complicated, autosomal recessive HSP triggering ER stress (Ito & Suzuki 2009, Yagi Troyer syndrome (SPG20) is caused by mu- et al. 2011), which may play a role in HSP tations resulting in a loss of spartin protein pathogenesis. LDs accumulate under various (Bakowska et al. 2008). Spartin localizes to cellular stress conditions, and a number of a variety of cellular structures and has been unfolded protein response pathways have implicated in a number of functions, including

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cytokinesis and epidermal growth factor there is a dramatic increase in oxysterol sub- (EGF) receptor trafficking (Robay et al. 2006, strates in plasma and cerebrospinal fluid (Schule¨ Bakowska et al. 2007, Renvoise´ et al. 2010, Lind et al. 2010). Given the fundamental roles played MIT domain: et al. 2011). Spartin also regulates LD biogene- by lipids and sterols in neuronal functions, it conserved domain sis by promoting atrophin-1 interacting protein seems very likely that more genes will be iden- comprising three 4 (AIP4)-mediated ubiquitination of LD pro- tified within this category. α-helices present in teins (Eastman et al. 2009, Edwards et al. 2009, microtubule- Hooper et al. 2010) and by recruiting PKC-ζ interacting and trafficking proteins via the PKC-ζ -interacting proteins ZIP1 Endosomal Dynamics (p62/sequestosome) and ZIP3 to LDs Although changes in ER morphology encom- ESCRT: endosomal sorting complex (Urbanczyk & Enz 2011). Little is known pass proteins altered in the majority of patients required for transport about any roles for LDs in axons. However, with HSP, more HSP proteins have been im- because the SPG17 protein seipin regulates plicated in endosomal dynamics; however, an LD formation, alterations in LD biogenesis immediate caveat is that the cell seems to co- or turnover could affect lipid distribution, opt some of these proteins and machineries organelle shaping, or signaling pathways for other functions (Blackstone et al. 2011). As important for axonal health. noted earlier, the SPG20 protein spartin func- Although not directly implicated in LD tions in LD turnover, but it is also required for biogenesis, other HSP proteins are enzymes efficient EGF receptor degradation and likely involved in related lipid and cholesterol biosyn- regulates EGF signaling (Bakowska et al. 2007). thetic pathways. SPG42 is caused by mutations Spartin may also regulate a variety of signaling in the SLC33A1 gene encoding the acetyl- pathways via ubiquitin modification through CoA transporter. In animals, acetyl-CoA is its interactions with E3 ubiquitin ligases such essential for maintaining the balance between as AIP4 and AIP5. Spartin harbors an MIT carbohydrate and fat metabolism. Under domain as well and interacts selectively with normal circumstances, acetyl-CoA from fatty IST1, a component of the ESCRT-III complex. acid metabolism enters the citric acid cycle, ESCRT comprises a series of cytosolic protein contributing to the energy supply of the cell. complexes, ESCRT-0, ESCRT-I, ESCRT-II, SLC33A1 transports acetyl-CoA into the Golgi and ESCRT-III, and the sequential activi- apparatus lumen and has been directly linked ties of these complexes are required to rec- to the growth of axons because knock down of ognize and sort ubiquitin-modified proteins slc33a1 in zebrafish causes defective outgrowth into internal vesicles of multivesicular bodies from the spinal cord (Lin et al. 2008). (Hurley & Hanson 2010). More recently, Last, neuropathy target esterase (NTE) is ESCRT proteins have been implicated in other an integral membrane protein of neuronal ER cellular functions, including viral budding and Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. that is mutated in autosomal recessive SPG39, a cytokinesis, and spartin has been shown to par- complicated HSP with prominent amyotrophy. ticipate in cytokinesis (Renvoise´ et al. 2010, NTE deacylates the major membrane phos- Lind et al. 2011). pholipid, phosphatidylcholine. Mutation of the This link to ESCRT-III is shared by the NTE gene PNPLA2 or chemical inhibition of SPG4 protein spastin. Although discussed ear- NTE with organophosphates alters membrane lier in the context of its interactions with composition and causes distal degeneration of REEP1 and atlastin-1 to coordinate ER mem- long spinal axons in mice and man (Rainier brane modeling and microtubule interactions et al. 2008, Read et al. 2009). Another HSP (Park et al. 2010), spastin harbors an MIT protein, cytochrome P450-7B1 (CYP7B1), domain that binds the ESCRT-III subunits is mutated in autosomal recessive SPG5 CHMP1B and IST1 to couple the severing of (Tsaousidou et al. 2008) and functions in microtubules with membrane scission. These cholesterol metabolism; in patients with SPG5 ESCRT interactions are crucial for spastin’s

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role in severing microtubules to complete the 2010). Thus, the WASH complex (containing abscission phase of cytokinesis (Yang et al. strumpellin) exemplifies another HSP protein 2008, Connell et al. 2009, Guizetti et al. 2011). functioning in coordinating membrane model- WASH complex: Wiscott-Aldrich ESCRT proteins are also involved in centro- ing and cytoskeletal organization. Strumpellin syndrome protein and some stability (Morita et al. 2010), raising the interacts with valosin-containing protein SCAR (suppressor of possibility that axon genesis and regulation (VCP/p97), an AAA ATPase mutated in cAMP receptor) by centrosomes could be a function of these frontotemporal dementia with Paget’s disease homolog complex proteins. Other possibilities include roles for of bone and inclusion body myopathy (Clemen Tubular transport the ESCRT-III interactions with spastin and et al. 2010), and VPS35 is mutated in a number intermediate: small, spartin in the delivery and downregulation of of families with autosomal dominant, late-onset cigar-shaped organelles that traffic cell surface receptors to regulate signaling in Parkinson disease (Vilarino-G˜ uell¨ et al. 2011, from one membrane axons. Zimprich et al. 2011). A causative mutation in compartment to Mutations in the KIAA1096 (SPG8) gene the WASH subunit SWIP has recently been another that encodes strumpellin cause a severe, pure identified for autosomal recessive intellectual HSP (Valdmanis et al. 2007). Strumpellin disability (Ropers et al. 2011). Thus, roles of the contains few motifs or domains of identified WASH-retromer axis in neurological disease function, aside from a region of putative clearly extend beyond the HSPs and represent spectrin repeats. The main clues to its pos- a very important area for investigation. sible endosomal functions stem from its Another emerging HSP-related complex identification as a subunit of the WASH related to endocytic trafficking comprises the complex (Derivery & Gautreau 2010). This SPG15 protein spastizin/FYVE-CENT, the complex, comprising seven subunits (five core SPG11 protein spatacsin, and the SPG48 pro- components), connects tubular endosomes of tein KIAA0415. Clinically, SPG11 and SPG15 retrograde cargo sorting to the cytoskeleton, share a number of characteristics; both are fre- and it associates with endosomes via an inter- quently associated with thin corpus callosum, action with vacuolar protein sorting–associated and both can present with juvenile parkin- protein 35 (VPS35) (Harbour et al. 2010). sonism. Spastizin and spatacsin colocalize in Along with VPS26 and VPS29, VPS35 is a cytoplasmic structures and were identified as component of retromer, an endosomal complex proteins that coprecipitate with the SPG48 responsible for sorting cargoes from endo- protein KIAA0415 (Slabicki et al. 2010, Murmu somes to the trans-Golgi network (Bonifacino et al. 2011). KIAA0415 was originally proposed & Hurley 2008). Depletion of members of the as a DNA helicase on the basis of sequence WASH complex cause increased tubulation at predictions (Slabicki et al. 2010), but a very early endosomes, impairing trafficking through recent study provides compelling evidence that early endosomal compartments (Derivery et al. it is a subunit of a new adaptor protein complex, Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. 2009, Gomez & Billadeau 2009, Jia et al. 2010). AP-5, involved in endosomal dynamics (Hirst Several members of the complex—WASH1, et al. 2011). Spastizin/FYVE-CENT contains FAM21 (family with sequence similarity 21), a FYVE domain and binds the lipid PI(3)P, and actin-capping protein—regulate actin dy- functioning along with ESCRT proteins in namics. The WASH complex helps generate an cytokinesis (Sagona et al. 2010). Along these actin network on early endosomes, for instance lines, mutations in multiple proteins of the by activating the Arp2/3 complex to nucleate AP-4 complex, which is involved in trafficking new actin filaments branching off extant of amyloid precursor protein from the trans- filaments. The increased tubulation associated Golgi to endosomes (Burgos et al. 2010), cause with WASH-complex depletion may reflect a autosomal recessive syndromes with prominent lack of actin-mediated forces that are required clinical features ranging from intellectual dis- for fission of tubular transport intermediates ability to progressive spastic paraplegia (Abou from the endosome (Campellone & Welch Jamra et al. 2011, Moreno-De-Luca et al.

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2011). Thus, these adaptor protein complexes motors or because they have reduced micro- appear highly relevant for pathogenesis of tubule binding affinity and act in a dominant- HSPs and other neurological diseases. negative manner by competing with wild-type Amyotrophic lateral Together, the expanding number of HSP motors for cargo binding (Ebbing et al. 2008). sclerosis (ALS): a genes implicated in endosome dynamics are degenerative disorder already revealing new relationships among affecting corticospinal protein complexes, with implications that Mitochondrial Function and lower motor extend beyond the primary HSPs. Indeed, a Mitochondrial dysfunction has been implicated neurons number of patients with familial amyotrophic in a host of developmental and degenerative lateral sclerosis (ALS) resulting from an neurological disorders, manifesting clinically as autosomal recessive mutation in the ALS2 peripheral neuropathies, movement disorders, gene encoding the alsin protein, a guanine visual disturbances, and cognitive disability (Di- nucleotide exchange factor (GEF) for the Mauro & Schon 2008). Given this fundamental small GTPases Rab5 and Rac1, have a disease link to neurological disease, it is surprising presentation more similar to the HSPs than to that so few HSP genes encode mitochondrial ALS. Examination of Als2 null mice revealed proteins. Two resident mitochondrial proteins motor impairments and a distal axonopathy of mutated in HSPs are paraplegin (autosomal the corticospinal tract. Rab5-dependent endo- recessive SPG7) and HSP60 (autosomal somal fusion is impaired in neurons from these dominant SPG13). Paraplegin is an m-AAA mice, whereas alsin overexpression in neurons metalloprotease of the inner mitochondrial stimulates Rab5-dependent endosomal fusion, membrane, where it functions in ribosomal resulting in enlarged endosomes (Devon et al. assembly and protein quality control. Muscle 2006, Deng et al. 2007, Hadano et al. 2007). tissue from SPG7 patients exhibits defects in oxidative phosphorylation and Spg7 null mice have axonal swellings with accumulated Motor-Based Transport mitochondria and neurofilaments, indicating The identification of mutations in the KIF5A that both mitochondrial function and axonal gene encoding kinesin heavy chain 5A (known transport are impaired (Ferreirinha et al. 2004). also as kinesin-1A) in families with SPG10, SPG13 is typically a late-onset, pure HSP, and a pure or complicated HSP, has provided a causative missense mutation (p.V98I) impairs direct evidence for motor-based transport HSP60 chaperonin activity, leading to impaired impairments underlying HSPs (Reid et al. mitochondrial quality contol (Bross et al. 2008). 2002, Goizet et al. 2009). KIF5 proteins are ATP-dependent motors that move cargoes in the anterograde direction along axons, and RELATED DISORDERS Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. most mutations are missense changes in the We have discussed the convergent pathways motor domain. Drosophila harboring mutations of many proteins mutated in HSPs, but it in the KIF5 ortholog Khc have posterior has become increasing clear that the HSP paralysis, with organelle-filled axon swellings presentation is often part of a broader disease jammed with cargoes (Hurd & Saxton 1996). spectrum; thus it is important to consider In mammals, the KIF5A motor protein shuttles related disorders that may share pathogenic neurofilament subunits along axons and possi- themes. Indeed, the importance of organelle bly other anterograde cargoes such as vesicles. morphology and distribution in maintaining KIF5 also regulates transport of cargoes in den- axons is also emphasized by other inherited drites and has roles in a number of membrane axonopathies, particularly peripheral nerve traffic pathways. The efficiency of cargo trans- disorders such as the Charcot-Marie-Tooth port to the distal axon is thought to be affected (CMT) neuropathies and hereditary sen- either because the mutated KIF5A are slower sory and autonomic neuropathies (HSAN).

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Mutations in the FAM134B gene were iden- CMT2 pedigree was reported with autosomal tified in some patients with HSAN II. The dominant mutation in DYNC1H1, which codes FAM134B protein is a member of the FAM134 for the dynein heavy chain 1 involved in retro- Bone morphogenetic protein (BMP): protein family, each of which contains a grade axonal transport (Weedon et al. 2011). amemberofthe pair of long hydrophobic segments reminis- Finally, ER shaping mechanisms may have transforming growth cent of those in ER-shaping reticulon and roles in related neurologic disorders such factor-β superfamily Yop1p/DP1/REEP proteins. FAM134B is as familial ALS, in which both corticospinal enriched in the cis-Golgi apparatus, and its and lower motor neurons are affected. In depletion causes prominent changes in Golgi the superoxide dismutase 1 (SOD1) G93A morphology in neurons (Kurth et al. 2009). transgenic mouse model for ALS, overexpres- More recently, homozygous loss-of-function sion of the ER-shaping protein reticulon-4A KIF1A mutations were identified in an Afghan selectively redistributed the ER chaperone family with HSAN II (Riviere` et al. 2011), and protein disulfide isomerase and protected the KIF1A protein is a motor involved in axonal against neurodegeneration. Conversely, loss transport of synaptic vesicles. A family has also of reticulon-4A increased disease severity been recently identified with hereditary spastic (Yang et al. 2009). Further supporting a role paraplegia caused by homozygous mutation for aberrant ER morphogenesis in neurologic in the KIF1A motor domain (Erlich et al. disorders, a mutant variant of vesicle-associated 2011), indicating that HSP and HSANs may, membrane protein–associated protein B (VAP- in at least some cases, fall along a phenotypic B) that underlies another familial ALS (ALS8) is spectrum. In fact, dominant missense muta- associated with the production of a novel form tions in the SPG3A protein atlastin-1 have of organized smooth ER (Fasana et al. 2010). been recently reported in hereditary sensory neuropathy (HSN) I (Guelly et al. 2011). More generally, these disorders highlight the E PLURIBUS UNUM? implications of morphological defects in the These divisions as discussed above are, of neces- ER and the early secretory pathway as well sity, somewhat arbitrary because cellular path- as distribution defects in the pathogenesis of ways show a great deal of interdependence, length-dependent axonopathies. and a number of HSPs can fit into several Pathogenic studies of CMT peripheral neu- pathogenic themes. For instance, the shaping ropathies are also instructive. CMT1 is com- phenomenon crosses over a number of cate- posed of demyelination disorders, and CMT2 is gories, from ER to endosomes. A natural ques- composed of those that cause axonopathies. Ax- tion is, then, can these be unified further? onal forms of CMT in particular can be caused by mutations in genes that encode proteins Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. that function in organelle morphogenesis and Bone Morphogenetic trafficking. CMT2A results from mutations in Protein Signaling the gene encoding mitofusin2 (MFN2), which One compelling candidate that crosses HSP regulates mitochondrial morphology by medi- categories and is widely implicated in neu- ating mitochondrial fusion and has also been rodegenerative diseases is bone morphogenetic implicated in mitochondrial connections with protein (BMP) signaling (Bayat et al. 2011). the ER (de Brito et al. 2010). The CMT2B HSP-associated mutations are found in at least protein Rab7, a small GTPase that regulates four proteins—atlastin-1, NIPA1 (nonim- endosomal vesicle trafficking, interacts with printed in Prader-Willi/Angelman syndrome the SPG21 protein maspardin, another HSP- 1; SPG6), spastin, and spartin—that function associated protein that localizes to endosomes as inhibitors of BMP signaling. In Drosophila (Hanna & Blackstone 2009, McCray et al. 2010, and mammals, BMP signaling functions in reg- Soderblom et al. 2010). Very recently, a large ulating axonal growth and synaptic function,

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and impairment of BMP signaling in Drosophila Interorganelle Contacts leads to axon transport defects (Wang et al. and Communication 2007). In rodents, BMP signaling is upregulated Another possibility for linking HSP themes fur- following lesioning of the corticospinal tract, ther is via interorganelle contacts. The ER is and suppression of this upregulation can pro- distributed promiscuously throughout the cell, mote regrowth of axons (Matsuura et al. 2008). and to mediate its many functions, it inter- Of the HSP proteins known to inhibit BMP acts with other organelles at specialized con- signaling, the best characterized mechanisti- tact sites. Such interactions occur with the cally is NIPA1, an integral membrane protein plasma membrane, mitochondria, and lyso- with 9 predicted TMDs that localizes to endo- somes/endosomes. The importance of these somes and the plasma membrane and functions connections for functions such as interorganelle in Mg2+ transport (Goytain et al. 2007). exchange of lipids/sterols, signal transduction, Drosophila larvae lacking spichthyin (NIPA1 or- + and mobilization of Ca2 stores is increas- tholog) have increased synaptic boutons at neu- ingly appreciated (Carrasco & Meyer 2011, romuscular junctions and increased phosphory- Toulmay & Prinz 2011). In particular, ER- lated MAD (mothers against decapentaplegic), mitochondrial contacts have been intensively a downstream messenger of BMP signaling. studied recently, with MFN2 in mammals These changes can be suppressed with genetic and an ER-mitochondrial encounter structure alterations that inhibit BMP signaling (Wang (ERMES) in yeast playing crucial roles (de et al. 2007). NIPA1/spichthyin is thought to Brito et al. 2010, Kornmann & Walter 2010). inhibit BMP signaling by promoting the inter- In a model of pulmonary arterial hyperten- nalization of BMP type II receptors and their sion, there was decreased ER-to-mitochondria subsequent lysosomal degradation, and NIPA1 phospholipid transfer and intramitochondrial missense changes found in SPG6 patients + Ca2 (Sutendra et al. 2011). The contacts be- interfere with this process, upregulating signal- tween mitochondria and ER were disrupted in ing. Similarly, depletion of spartin or spastin, a manner dependent on increased expression which both localize partially to endosomes, of an ER-shaping protein of the reticulon fam- upregulates BMP signaling (Tsang et al. 2009). ily, Nogo-B, linking changes in an ER-shaping Dysregulated BMP signaling linked to ax- protein to mitochondrial dysfunction. onal abnormalities has also been demonstrated for atlastin. Depletion of atlastin-1 in zebrafish resulted in abnormal spinal motor axon mor- phology, with increased branching and de- CONCLUDING REMARKS creased larval mobility. BMP signaling was up- The HSPs have recently been called a regulated in these larvae, and pharmacological “paradigmatic” example of how a disease can Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. or genetic inhibition of BMP signaling rescued foster insights into fundamental cellular pro- the atl1 null phenotype (Fassier et al. 2010). In cesses, particularly with regard to formation sum, these results suggest that abnormal BMP of the tubular ER network (De Matteis & signaling, probably caused by abnormal BMP Luini 2011). Ongoing studies investigating receptor trafficking in many cases, could be a how the ER network is shaped in neurons unifying mechanism for some classes of HSP, using electron microscopy reconstruction or including the two most common, SPG4 and super-resolution confocal microscopy will SPG3A, which comprise almost 50% of pa- improve our understanding of the appearance, tients. Investigating relevant HSP animal mod- contacts, and dynamics of ER in axons. With els will be critical to determine whether inhi- the increasing throughput and falling cost bition of BMP signaling using small-molecule of next-generation sequencing technologies, inhibitors, several of which are available, can more genes for HSPs and related disorders rescue disease phenotypes. will assuredly be uncovered, likely many more.

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Important insights into endocytic trafficking in HSP patients will be challenges for assessing pathways in particular seem sure to follow. the efficacy of therapies, but emerging noninva- With some compelling cellular mechanisms sive stimulation (triple stimulation technique) already identified, pharmacologic manipulation and imaging modalites such as diffusion ten- of these pathways and evaluations in cellular and sor imaging (Duning et al. 2010, Unrath et al. animal models will be increasingly important. 2010) might be useful biomarkers, particularly Pathways such as BMP signaling and micro- because they can detect changes in patients with tubule stability (Orso et al. 2005, Yu et al. 2008) known HSP mutations at a presymptomatic currently seem to be particularly attractive tar- phase, when disease-modifying therapies would gets because they would likely relate to a sig- be most useful (Duning et al. 2010). The past nificant percentage of HSP patients and seem several years have yielded remarkable advance- amenable to regulation by small molecules, ments in our understanding of the pathogenesis which could ultimately lead to therapies. underlying the HSPs; with increasing interest Animal models may be a particular challenge in the fascinating biology of HSP proteins and for HSPs because successfully modeling a dis- technological advances in genetics and imaging ease of 1 m axons in small rodents is not a moving rapidly, the future is hopeful for those given. The slow, variable rates of progression afflicted.

DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS I thank Alan Hoofring for preparing the figures. Work in the author’s laboratory is funded by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

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RELATED RESOURCES Neuromuscul. Dis. Cent. Web page. Familial spinal cord syndromes. http://neuromuscular. wustl.edu/spinal/fsp.html. A comprehensive, frequently updated resource for information on all types of HSPs and related disorders. Reid E, Rugarli EI. 2010. Hereditary spastic paraplegias. In The Online Metabolic and Molecular Bases of Inherited Diseases, ed. D Valle, AL Beaudet, B Vogelstein, KW Kinzler, SE Antonarakis, et al., Ch. 228.1. New York: McGraw Hill. http://dx.doi.org/10.1036/ommbid.266 Spastic Paraplegia Found. Web page. http://www.sp-foundation.org. Valuable information on research efforts focusing on the HSPs. Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only.

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Annual Review of Contents Neuroscience Volume 35, 2012

The Neural Basis of Empathy Boris C. Bernhardt and Tania Singer pppppppppppppppppppppppppppppppppppppppppppppppppppppppp1 Cellular Pathways of Hereditary Spastic Paraplegia Craig Blackstone pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp25 Functional Consequences of Mutations in Postsynaptic Scaffolding Proteins and Relevance to Psychiatric Disorders Jonathan T. Ting, Jo˜ao Pe¸ca, and Guoping Feng pppppppppppppppppppppppppppppppppppppppppp49 The Attention System of the : 20 Years After Steven E. Petersen and Michael I. Posner ppppppppppppppppppppppppppppppppppppppppppppppppppp73 Primary Visual Cortex: Awareness and Blindsight David A. Leopold ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp91 Evolution of Synapse Complexity and Diversity Richard D. Emes and Seth G.N. Grant ppppppppppppppppppppppppppppppppppppppppppppppppppp111 Social Control of the Brain Russell D. Fernald pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp133 Under Pressure: Cellular and Molecular Responses During Glaucoma, a Common Neurodegeneration with Axonopathy Robert W. Nickells, Gareth R. Howell, Ileana Soto, and Simon W.M. John ppppppppppp153 Early Events in Axon/Dendrite Polarization Pei-lin Cheng and Mu-ming Poo pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp181 Mechanisms of Gamma Oscillations Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. Gy¨orgy Buzs´aki and Xiao-Jing Wang ppppppppppppppppppppppppppppppppppppppppppppppppppppp203 The Restless Engram: Consolidations Never End Yadin Dudai pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp227 The Physiology of the Axon Initial Segment Kevin J. Bender and Laurence O. Trussell pppppppppppppppppppppppppppppppppppppppppppppppp249 Attractor Dynamics of Spatially Correlated Neural Activity in the Limbic System James J. Knierim and Kechen Zhang ppppppppppppppppppppppppppppppppppppppppppppppppppppp267 Neural Basis of Reinforcement Learning and Decision Making Daeyeol Lee, Hyojung Seo, and Min Whan Jung ppppppppppppppppppppppppppppppppppppppppp287

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Critical-Period Plasticity in the Visual Cortex Christiaan N. Levelt and Mark H¨ubener ppppppppppppppppppppppppppppppppppppppppppppppppp309 What Is the Brain-Cancer Connection? Lei Cao and Matthew J. During pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp331 The Role of Organizers in Patterning the Nervous System Clemens Kiecker and Andrew Lumsden ppppppppppppppppppppppppppppppppppppppppppppppppppp347 The Complement System: An Unexpected Role in During Development and Disease Alexander H. Stephan, Ben A. Barres, and Beth Stevens pppppppppppppppppppppppppppppppp369 Brain Plasticity Through the Life Span: Learning to Learn and Action Video Games Daphne Bavelier, C. Shawn Green, Alexandre Pouget, and Paul Schrater ppppppppppppp391 The Pathophysiology of Fragile X (and What It Teaches Us about Synapses) Asha L. Bhakar, G¨ul D¨olen, and Mark F. Bear pppppppppppppppppppppppppppppppppppppppppp417 Central and Peripheral Circadian Clocks in Mammals Jennifer A. Mohawk, Carla B. Green, and Joseph S. Takahashi pppppppppppppppppppppppp445 Decision-Related Activity in Sensory Neurons: Correlations Among Neurons and with Behavior Hendrikje Nienborg, Marlene R. Cohen, and Bruce G. Cumming pppppppppppppppppppppp463 Compressed Sensing, Sparsity, and Dimensionality in Neuronal Information Processing and Data Analysis Surya Ganguli and Haim Sompolinsky ppppppppppppppppppppppppppppppppppppppppppppppppppp485 The Auditory Ribbon Synapse: From Assembly to Function Saaid Safieddine, Aziz El-Amraoui, and Christine Petit pppppppppppppppppppppppppppppppp509 Multiple Functions of Endocannabinoid Signaling in the Brain Istv´an Katona and Tam´as F. Freund pppppppppppppppppppppppppppppppppppppppppppppppppppppp529 Annu. Rev. Neurosci. 2012.35:25-47. Downloaded from www.annualreviews.org by National Institutes of Health Library (NIH) on 06/21/12. For personal use only. Circuits for Skilled Reaching and Grasping Bror Alstermark and Tadashi Isa pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp559

Indexes Cumulative Index of Contributing Authors, Volumes 26–35 ppppppppppppppppppppppppppp579 Cumulative Index of Chapter Titles, Volumes 26–35 ppppppppppppppppppppppppppppppppppp583

Errata An online log of corrections to Annual Review of Neuroscience articles may be found at http://neuro.annualreviews.org/

viii Contents