Polyglutamine Diseases and Transport Problems Deadly Traffic Jams on Neuronal Highways

BASIC SCIENCE SEMINARS IN NEUROLOGY

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Polyglutamine Diseases and Transport Problems Deadly Traffic Jams on Neuronal Highways

Shermali Gunawardena, PhD; Lawrence S. B. Goldstein, PhD

he expansion of CAG repeats encoding glutamine (polyQ) causes, to date, 9 late-onset progressive neurodegenerative disorders, including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. Although many studies using both knockout and transgenic mouse Tmodels suggest that a toxic gain of function is central to neuronal dysfunction, the exact mecha- nisms of neurotoxic effects remain elusive. Protein aggregations within neurons seem to be a common manifestation in almost all polyQ diseases, and such accumulations are perhaps major triggers of cellular stress and neuronal death. Recent data lead to the tantalizing proposal that disruption of axonal transport pathways within long, narrow-caliber axons could lead to protein accumulations that can elicit neuronal death, ultimately causing a neuronal dysfunction pathway observed in polyQ expanded diseases. Perhaps perturbations in transport pathways are an early event involved in instigating polyQ disease pathology. Arch Neurol. 2005;62:46-51

Our nervous system can be thought of as dynein and some kinesin motors. Since requiring a transport system composed of transport of cargoes is required for cell vi- highways that transport essential cargoes ability, it is conceivable that disruption in from a central station, cell bodies in the this long distance transport system can lead spinal cord or brain, to places of need, to disease pathology observed in many nerve terminals or synapses, very much neurodegenerative diseases, including like a busy freeway system. Most materi- polyglutamine (polyQ) diseases. als within axons or synapses are synthe- sized within the neuronal cell body and AXONAL TRANSPORT PATHWAYS are moved along lengthy axons to sites of AND NEURODEGENERATIVE function. Molecular motors, such as ki- DISEASE nesin and dynein, are proteins that power cargo transport and use adenosine triphos- The importance of the axonal transport sys- phate hydrolysis to move vital cargoes on tem in disease states has been recently high- microtubule tracks (Figure 1). Within lighted by several intriguing studies. These axons, organelles, vesicles, cytoskeletal studies not only suggest that strangulation proteins, signaling molecules, and other of the axon may led to disease pathology but supplies from the cell body are trans- also implicate components of the axonal ported by kinesin motors in the antero- transport machinery as targets for the devel- grade direction to nerve terminals and syn- opment of human disease. Mutations in apses, while signaling molecules and other KIF1Bβresult in Charcot-Marie-Tooth dis- components that need to be returned to ease type 2A, which is characterized by pro- the cell body from synapses are trans- gressive dysfunction of peripheral neurons, ported in the retrograde direction by possibly owing to the reduced transport of synaptic vesicle precursors.1 A missense mu- Author Affiliations: Howard Hughes Medical Institute, Department of Cellular and tation in the neuronal kinesin heavy chain Molecular Medicine, School of Medicine, University of California, San Diego, gene KIF5A results in hereditary spastic La Jolla. paraplegia, a condition that arises owing to

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 axonaldegenerationofmotorandsen- Vesicles, Cytoskeleton, RNA, Signaling Proteins, sory neurons at the distal ends of the Neuroprotective and Repair Molecules longest axons of the central nervous system.2 In a dynamitin (a component of the dynactin complex that interacts with dynein) overexpressing mouse Cargos 3 model, excessdynamitindisassembles Cell Body Anterograde Synapse dynactinandinhibitsretrogradetrans- Kinesin port, suggesting that impediment of – + axonal transport is sufficient to cause Dynein motor neuron degeneration observed Retrograde

inamyotrophiclateralsclerosis.While Cargos mice with transgenic amyotrophic lat- eral sclerosis showed abnormalities in microtubule-basedtransport,withde- creased rates of slow axonal transport Vesicles, Protein Complexes, Signaling Proteins, and degeneration of motor neurons,4 Neuroprotective and Repair Molecules the dynamitin transgenic mice demonstrate a late-onset progressive mo- Figure 1. Microtubule-based transport within the axon. The plus-end motor kinesin transports cargoes 3 anterogradely while those that need to be brought back to the cell body are transported by the minus-end tor neuron degenerative disease. A motor dynein and some kinesins. mutation in the human dynactin gene DCTN1 causes human motor neuron the observation that PS, a component (except for spinobulbar muscular at- disease,5 and missense mutations in of the ␥-secretase complex, interacts rophy), typically begin in midlife, and cytoplasmic dynein heavy chain with GSK3␤.10 An enhancement in result in severe neuronal dysfunc- (Dnchc1) cause selective impairment GSK3␤ activation and a deficiency in tion and neuronal cell death. The ex- of axonal retrograde transport, cell kinesin-1–mediatedtransportwereob- panded trinucleotide repeats are un- death,Lewybody–likeinclusions,and served in PS mutations that cause stable, with increased repeat length progressive motor neuron degenera- familial AD (FAD).11 Intriguingly, correlating with worsening of the dis- tion.6 Together, these studies argue GSK3␤ phosphorylates kinesin light ease phenotype. The polyQ expan- that axonal transport failure can be a chainsleadingtothedissociationofki- sion is believed to confer a toxic gain causative feature in neurodegenera- nesin from membranes.12 Perhaps the of function, perhaps causing an in- tivedisease,strengtheningtheproposal disassociationofkinesinfromAPP-PS– creased propensity for the mutant that disruption of axonal transport is containing vesicles results in the fail- protein to misfold and aggregate. Al- an important determinant in the ini- ure of transport in FAD-PS mutants. though all 9 polyQ diseases are ge- tiation and perhaps the progression of Together, these observations suggest netically distinct and can be charac- pathogenesis. thattheaxonaltransportpathwaymay terized by their specific lesion Axonal transport problems have becentraltothepathogenesisobserved distributions in the nervous system, also been implicated in Alzheimer dis- in AD. recent studies indicate that except for ease(AD).Recentworkfromourlabo- Disruptions in transport path- spinocerebellar ataxia (SCA) types 2 ratory demonstrates that the amyloid ways could also be involved in the and 6, the formation of intranuclear precursor protein (APP) can function pathogenesis of Huntington disease inclusions within neurons is a com- as a kinesin-I receptor.7,8 In Drosophila (HD) and other polyQ expansion dis- mon hallmark of all 9 diseases. overexpression of wildtype human eases. Since protein aggregates are a Nuclear inclusions have been found APP or familial mutations responsible common feature in all polyQ dis- in neuronal populations susceptible for AD (Swedish and London) cause eases, it is conceivable that failure in to the disease process, and this has axonal vesicle accumulations, which the transport system may also result lead to the widespread belief that in- contain APP and trigger neuronal cell in polyQ pathogenesis. Herein we tranuclear aggregations are central to death.8 Secretases(␤-secretaseandpre- briefly highlight polyQ disease pa- polyQ pathogenesis. senilin [PS]) that are responsible for thology and discuss several recent ad- Clinically, polyQ disorders share thegenerationofpathogenicamyloid-␤ vances relating this pathology to pos- several common features, including (A␤) appear to be present in APP sible transport problems. slow progression and late (adult) on- vesicles.9 Perhaps axonal blockages set. They also exhibit anticipation, be- containing APP vesicles are sites of A␤ PolyQ PROTEINS AND coming earlier and/or more severe in production, and processing of APP DISEASE PATHOLOGY succeeding generations, which is cor- within these sites leads to the dissocia- related with an intergenerational in- tion of kinesin from APP vesicles lead- Polyglutamine repeat diseases are a crease in repeat length. Each of the ing to the failure of transport within class of hereditary neurodegenera- polyQ disorders affect specific but narrow axons, thus triggering the in- tive diseases caused by the expan- overlapping regions of the brain. The duction of neuronal dysfunction or sion of CAG triplet repeats encoding clinical pathologic features of spi- death. a polyglutamine tract in the normal nobulbar muscular atrophy is rela- Yet another link between AD and protein (Table). These disorders are tively distinct, whereas that of axonaltransportproblemscomesfrom progressive, dominantly inherited dentatorubral-pallidoluysian atro-

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Protein Disorder Protein Location/Expression Function Inclusions Huntington disease Huntingtin Ubiquitous cytoplasmic/ Axonal transport ? Dystrophic striatal, corticostriatal mostly in neurons neurons (CI and NI) Spinocerebellar ataxia Type 1 Ataxin-1 Neuronal nuclei ? Purkinje neurons (CI and NI) and peripheral tissue Type 2 Ataxin-2 Purkinje cells ? ? Type 3 Ataxin-3 Ubiquitous cytoplasmic ? Ventral pons (CI and NI) + Type 6 ␣1A Ca channel P/Q Central nervous system Homeostasis and Purkinje neurons (CI only) signaling Type 7 Ataxin-7 Ubiquitous nuclear ? Cerebral cortex (CI and NI) Type 17 TBP Ubiquitous nuclear TATA binding Inferior olivay complex and cerebral protein ? cortex (NI) Dentatorubral-pallidoluysian Atrophin-1 Ubiquitous cytoplasmic ? Dentate (NI) atrophy Spinobulbar muscular Androgen receptor Motor neurons Development and Motor neurons (CI and NI) atrophy growth

Abbreviations: Ca+, calcium; CI, cytoplasmic inclusions; NI, nuclear inclusions; PolyQ, polyglutamine.

phy overlaps HD, and SCAs (re- VIEWS OF NEUROTOXIC Sequestration of cellular factors away viewed in Evert et al13). Involuntary EFFECTS IN PolyQ DISEASE from their usual locations into ag- movements, intellectual impair- gregates are proposed to compro- ment, and emotional disturbances Although little is known about the mise their function and cause toxic clinically characterize HD, while spi- mechanism by which polyQ expan- effects; (2) recruitment of transcrip- nobulbar muscular atrophy is a rare sion leads to pathogenesis, one pro- tion factors into aggregates are pro- progressive neuromuscular disor- posal is that misfolding of the mutant posed to attenuate transcription fac- der characterized by proximal weak- protein triggers a cascade of events, tor function; and (3) accumulation ness, atrophy, and fasciculations. which ultimately leads to disease pa- of molecular chaperones and pro- Dentatorubral-pallidoluysian atro- thology(reviewedinEvertetal13).The teosomes into aggregates are pro- phy is characterized by progressive misfolded protein may undergo proposed to limit their availability in the dementia, myoclonic epilepsy, cer- teolytic cleavage, interact with other cell, leading to diminished clear- ebellar ataxia, and choreoathetotic proteins, self-aggregate, and these ag- ance and harmful accumulation of movements. All SCAs exhibit vari- gregates may later translocate into the misfolded or damaged proteins, able degrees of cerebellar and brain- nucleus. Although the propensity of eventually activating cellular stress stem degeneration accompanied by polyQ proteins to aggregate is a com- response pathways and inducing progressive cerebellar ataxia associ- mon feature observed in all 9 polyQ apoptosis. ated neurological signs including expansion diseases, it remains unclear In contrast, however, many re- ophthalmoplegia, dementia, and ex- whetheraggregates,whichcontainnot cent studies propose that neuronal trapyramidal signs. only mutant protein but components dysfunction occurs before aggre- At the molecular level, polyQ dis- of the ubiquitin-proteosome pathway, gate formation. Prior to the detec- ease proteins are expressed ubiqui- chaperones,transcriptionalregulators, tion of aggregates, neuronal and be- tously throughout the brain and and other polyQ-containing proteins, havioral problems were detected in other tissues, although the normal are the cause of pathogenesis or the knock-in HD mice with 94 CAG re- function of most of these proteins re- end result of a cascade of events. In- peats,17 in SCA1 mice with 154 CAG mains unknown (Table). Excep- deed, Wanker14 postulates that aggre- repeats,18 and in SCA7 mice with 266 tions are the androgen receptor in gates themselves are neurotoxic even CAG repeats.19 Indeed, another spinobulbar muscular atrophy, the though the distribution of aggregates model suggests that aggregation of P/Q-type calcium channel subunit in withinthecentralnervoussystemdoes polyQ proteins may initially func- SCA6, and, based on recent work the not completely match areas of neuro- tion as beneficial “sinks” that acti- huntingtin protein. Except for SCA3, nal loss.15 vate degradation pathways, which the polyQ tract is located toward the Whatever the cause, most pro- may later become defective owing to N-terminal region of the protein in posals for disease mechanism in- overactivation, ultimately result- all polyQ diseases. Apart from the clude the hypothesis that aggre- ing in neuronal dysfunction.20 Since polyQ tract, the polyQ proteins do gates alone are a precondition of ubiquitin and components of the not share any other common fea- neurotoxic effects, and several mod- proteosome were observed to colo- tures. In the case of SCA3 and HD, els propose that dysfunction origi- calize with aggregates, further ag- cleavage of the mutant protein is nates from aggregate formation (re- gregation of polyQ proteins might thought to promote aggregation. viewed in Tarlac and Storey16): (1) block the degradation pathway.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 An important point of contro- versy is whether neuronal toxic effects observed in polyQ diseases results from nuclear or cytoplasmic events. The most common type of aggregates observed in polyQ disease are intranuclear, but these may Normal Transport occur later in disease progression owing to problems or failures in other pathways. Indeed, neuropil aggregates were observed with expanded polyQ repeats in the context of the androgen receptor21 in transgenic HD mice and in HD- Stalling of Vesicles Titration affected patient brains before the on- Cell Death of Normal Proteins? Neuronal Dysfunction Cytoplasmic Inclusions? set of clinical problems.22,23 Simi- larly, Klement et al24 demonstrate that while nuclear localization of Figure 2. Disruption of transport within narrow-caliber, long axons could lead to stalling of vesicles and ataxin-1 is necessary, nuclear aggre- formation of cytoplasmic inclusions within axonal processes, which may ultimately lead to neuronal death gation of ataxin-1 is not required for and dysfunction. Thus, accumulation of organelles within axonal processes may instigate an early initial pathogenesis in transgenic neurodegenerative disease pathway.

SCA1 mice. Consistent with these 28 findings are recent results demon- CAN AXONAL TRANSPORT Galarza et al showed that hunting- strating that both cytoplasmic and DEFECTS CAUSE PolyQ tin, the protein that causes HD, was nuclear accumulation pathways can DISEASE PATHOLOGY? transported both anterogradely and retrogradely in rat sciatic nerve axons. independently lead to neuronal dys- Although genes encoding motor pro- Immunolocalization studies in hu- function25 and that cytoplasmic ac- teins may be key players in human man and rat brains revealed cytoplas- cumulations precede nuclear inclu- diseases when mutated, it is possible mic huntingtin within neurons, and sions.26 Thus, cytoplasmic that proteins that regulate or inter- biochemical analyses indicated that accumulations may be the primary act with motor proteins may also huntingtin was enriched in compart- events in toxic effects. However, it cause disease when mutated. Alter- ments containing vesicle-associated is still unknown if protein cleavage natively, abnormal interactions of pro- proteins.29,30 Recently our laboratory plays a role, and if aberrant cleav- teins not normally functioning in found that normal Drosophila hun- age of N-terminal fragments con- transport could cause transport prob- tingtin functions in the axonal trans- taining pathogenic polyQ repeats are lems subsequently leading to neuro- port pathway, perhaps to transport the cause of cytoplasmic inclusion nal defects. Indeed, the widespread a subclass of vesicles.25 Although how formation and disease pathology. occurrence of axonal (or dendritic) in- huntingtin associates with the axo- Perhaps the cytoplasmic accumula- clusions observed in polyQ diseases nal transport machinery is still un- tions observed within axons are sites raises the possibility that perturba- clear, it can be proposed that hunting- of N-terminal cleavage, and these tions of transport pathways are an tin may associate with motor proteins pathogenic N-terminal fragments early susceptibility factor in disease via HAP1, a protein that has been then promote nuclear entry and ac- pathology. In fact, new work leads to shown to interact with both hunting- tivate transcriptional processes, the proposal that stalling of vesicles tin and the p150 subunit of dynac- which may lead to nuclear-medi- within narrow caliber axons triggers tin,27 thereby enabling retrograde ated toxic events.22,25,27 aggregate formation within axons, transport and perhaps anterograde Viewed broadly, an intriguing fea- which could then initiate a cascade of transport.31 HAP1 itself is transported ture of polyQ disease is that while events, resulting in neuronal death both anterogradely and retrogradely disease-causing genes are widely ex- and dysfunction Figure 2).25 There and also associates with vesicles and pressed (Table), only neurons are af- are 2 complementary aspects to this with microtubules.28,32,33 Intriguingly, fected. These observations raise the proposal: (1) disease-causing pro- mutations in the Drosophila HAP1- question of whether the specificity teins may have normal functions in like protein, Milton, causes axonal observed is due to the nature of the the axonal transport system and may transport defects and may function neuron, with its long narrow axo- cause axonal blockages when al- in the transport of mitochondria to nal and dendritic processes. Essen- tered; and (2) “sticky” diseased pro- synapsesbybindingtokinesin.34 Thus tial components must be trans- teins may physically block transport huntingtin and HAP1 may have vi- ported over great distances in axons within narrow axonal processes, and tal roles in axonal transport and per- and dendrites along microtubule also titrate normal proteins, instigat- haps with dynactin they have a role tracks for cell viability. Perhaps de- ing pathways that lead to subse- inestablishingbidirectionaltransport. fects in this transportation system quent neuronal problems. Pathologic evidence for axonal have long-term effects on polyQ dis- Many observations support these transport problems in HD comes ease pathology. proposals for HD. In 1997, Block- from observations in transgenic HD

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 mouse models and human patient In addition, expression of different tion in a variety of polyQ disease mod- brains. Several groups have demon- pathogenicpolyQproteinswithinDro- els including yeast, Caenorhabditis el- strated that dystrophic striatal and sophila neurons cause axonal block- egans, Drosophila, and mouse corticostriatal neurites in HD ex- ages, which increase with reductions (reviewed in Bates and Hockly42). hibit characteristics of blocked axons, in motor proteins and reduce the Current potential therapeutic inter- namely, accumulations of vesicles amountofmotorproteinsavailablefor ventions targeting specific molecu- and organelles in swollen axonal pro- normaltransport.25 Theseobservations lar events include minocycline (a jections and termini in association suggest that accumulations of disease caspase 1 inhibitor), cystamine (an in- with huntingtin aggregates.30,35 Hun- proteins, perhaps those that are sticky, hibitor of tissue transglutaminase), tingtin accumulations have been can physically block transport path- Congo red (an inhibitor of polyQ ag- found in axons of striatal projection ways and titrate motors proteins away gregation), and suberoylanilide hy- neurons in R6/2 and knockin mouse from their normal functions within droxamic acid (a hydroxamic acid in- models of HD and in human patient narrow-caliberaxonsordendriticpro- hibitor) (reviewed in Bates and brains.23 These striatal axonal inclu- cesses.Consistentwiththisidea,itwas Hockly42). It is still unknown if these sions are better correlated with stria- recently shown that cytoplasmic hun- compounds act on the target for tal neuronal loss than the presence tingtin aggregates trap or titrate polyQ which they were selected. While it is of nuclear inclusions. Intriguingly, proteins, which may further block important to distinguish if transport the axonal pathology observed in transport pathways.41 Thus, the 2 failures are an early secondary prob- striatal neurons is virtually identical pathogenic pathways suggested by the lem as opposed to being the true ini- to the phenotype of motor protein transport hypothesis (described ear- tiating cause of polyQ disease, phar- mutants in Drosophila and polyQ- lier) may not be mutually exclusive. macological interventions directed induced axonal blockages found in Although transport problems toward the transport process may be Drosophila models of polyQ dis- cannot account for all aspects of valuable in the development of thera- ease.25,36 polyQ disease pathology, they pro- pies. An important first step is to test Although little is known about vide a plausible explanation for how if any of the above compounds pre- how these phenotypes arise and failures in the transport system could vent axonal transport problems in the whether these observations are an result in neuronal loss. Future ex- in vivo Drosophila model system, early indication of neurodegenera- periments should focus on investi- which exhibits specific axonal trans- tion or the initial step in a cascade of gating axonal transport problems in port phenotypes within polyQ ex- events that cause dysfunction, these other polyQ diseases for which ex- pressing neurons.25 Ultimately, it is findings together with the evidence cellent animal models are available critical to develop axonal transport as- for cytosolic localization of full- and for which human tissues are says in living patients. length huntingtin protein and its as- readily accessible. Since different sociation with cytoskeletal and ve- motor proteins move a variety of car- Accepted for Publication: August 5, sicular structures are compelling goes, including membrane organ- 2004. arguments for a role of axonal trans- elles, protein complexes, com- Correspondence: Lawrence S. B. port in the pathology of HD. Since plexes of nucleic acids, signaling Goldstein, PhD, Howard Hughes mutant huntingtin was shown to in- molecules, neuroprotective and re- Medical Institute, Cellular and Mo- terfere with its anterograde trans- pair molecules and cytoskeletal com- lecular Medicine West, Room 336, port, contributing to the depletion of plexes along microtubule tracks, the University of California, San Diego, brain-derived neurotrophic factor in susceptibility of different neurons to 9500 Gilman Dr, La Jolla, CA 92093- the striatum,37 perhaps normal hun- different polyQ disease may result 0683 ([email protected]). tingtin is required for efficient vesicle owing to the specialized function of Author Contributions: Study con- trafficking of cortical brain-derived the normal protein within those neu- cept and design: Gunawardena and neurotrophic factor. Indeed, a re- rons. Thus, rigorous investigations Goldstein. Analysis and interpreta- cent study supports this proposal.38 are needed to elucidate the normal tion of data: Gunawardena and Gold- A similar mechanism can be pro- functions of proteins involved in stein. Drafting of the manuscript: Gu- posedforotherpolyQdiseases.Expres- polyQ diseases, in particular to de- nawardena. Critical revision of the sion of expanded polyQ repeats in the termine if these are involved in the manuscript for important intellec- context of the androgen receptor also axonal transport pathway. tual content: Gunawardena and causes neuropil aggregates and alters Goldstein. Obtained funding: Gold- the distribution of kinesin.21 Consis- EXPERIMENTAL stein. Administrative, technical, and tent with this, recent data from Szebe- THERAPEUTICS AND THEIR material support: Gunawardena. nyi et al39 demonstrate a polyQ length- EFFECT ON AXONAL Study supervision: Goldstein. dependent inhibition of anterograde TRANSPORT AND PolyQ Funding/Support: This study was and retrograde transport in isolated DISEASE PATHOLOGY supported by a fellowship from the squid axoplasm by truncated versions Wills Foundation, Houston, Tex, of huntingtin or the androgen recep- Although it is still not understood and by a senior postdoctoral fellow- tor.InSCA6,axonalaccumulationsare how polyQ disease pathology is ship from the Ellison Medical Foun- observed that appear to contain accu- caused, several groups have focused dation/American Federation for Ag- mulationsofneurofilamentsandother on identifying chemical agents that ing Research (AFAR), New York, NY materials that fail to be transported.40 modulate cell toxicity or aggrega- (Dr Gunawardena). Dr Goldstein is

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 an investigator of the Howard polyglutamine diseases. Cell Tissue Res. 2000; 29. DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a Hughes Medical Institute, Chevy 301:189-204. cytoplasmic protein associated with vesicles in hu- 14. Wanker EE. Protein aggregation and pathogen- man and rat brain neurons. Neuron. 1995;14: Chase, Md. esis of Huntington’s disease: mechanism and 1075-1081. Acknowledgments: We apologize to correlations. Biol Chem. 2000;381:937-942. 30. DiFiglia M, Sapp E, Chase KO, et al. Aggregation those authors whose work was not 15. Kuemmerle S, Gutekunst CA, Klein AM, et al. of huntingtin in neuronal intranuclear inclusions cited owing to space limitations. Huntington aggregates may no predict neuronal and dystrophic neurites in brain. Science. 1997; death in Huntington’s disease. Ann Neurol. 1999; 277:1990-1993. 46:842-849. 31. Gunawardena S, Goldstein LS. Cargo-carrying mo- 16. Tarlac V, Storey E. Role of proteolysis in polyglu- REFERENCES tor vehicles on the neuronal highway: transport tamine disorders. J Neurosci Res. 2003;74: pathways and neurodegenerative disease. 406-416. J Neurobiol. 2004;58:258-271. 1. Zhao C, Takita J, Tanaka Y, et al. Charcot-Marie- 17. Menalled LB, Sison JD, Wu J, et al. Early motor 32. Li X, Sharp AH, Li SH, Dawson TM, Snyder SH, Tooth disease type 2A caused by mutation in a dysfunction and striosomal distribution of hun- Ross CA. Huntingtin-associated protein (HAP1): ␤ microtubule motor KIF1B . Cell. 2001;105:587- tingtin microaggregates in Huntington’s disease discrete neuronal localizations in the brain re- 597. knock-in mice. J Neurosci. 2002;22:8266-8276. semble those of neuronal nitric oxide synthase. 2. Reid E, Kloos M, Ahley-Koch A, et al. A kinesin 18. Watase K, Weeber EJ, Xu B, et al. A long CAG re- Proc Natl Acad Sci U S A. 1996;93:4839-4844. heavy chain (KIF5A) mutation in hereditary spas- peat in the mouse SCA1 locus replicates SCA1 fea- 33. Engelender S, Sharp AH, Colomer V, et al. Hun- tic paralegia (SPG10). Am J Hum Genet. 2002; tures and reveals the impact of protein solubility tingtin-associated protein 1 (HAP1) interacts with 71:1189-1194. on selective neurodegeneration. Neuron. 2002; the p150Glued subunit of dynactin. Hum Mol 3. LaMonte BH, Wallace KE, Holloway BA, et al. 34:905-919. Genet. 1997;6:2205-2212. Disruption of dynein/dynactin inhibits axonal trans- 19. Yoo SY, Pennesi ME, Weeber EJ, et al. SCA7 34. Stowers RS, Megeath LJ, Gorska-Andrzejak J, Mei- port in motor neurons causing late-onset pro- knockin mice model human SCA7 and reveal nertzhagen IA, Schwarz TL. Axonal transport of gressive degeneration. Neuron. 2002;34:715- gradual accumulation of mutant ataxin-7 in neu- mitochondria to synapses depends on milton, a 727. rons and abnormalities in short-term plasticity. novel Drosophila protein. Neuron. 2002;36:1063- 4. Williamson TL, Cleveland DW. Slowing of axonal Neuron. 2003;37:383-401. 1077. transport is a very early event in the toxicity of ALS- 20. Chen S, Berthelier V, Yang W, Wetzel R. Polyglu- 35. Sapp E, Penney J, Young A, Aronin N, Vonsattel linked SOD1 mutants to motor neurons. Nat tamine aggregation behavior in vitro supports a JP, DiFiglia M. Axonal transport of N-terminal hun- Neurosci. 1999;2:50-56. recruitment mechanism of cytotoxicity. J Mol Biol. 5. Puls I, Jonnakuty C, LaMonte BH, et al. Mutant 2001;311:173-182. tingtin suggests early pathology of corticostria- dynactin in motor neuron disease. Nat Genet. 2003; 21. Piccioni F, Pinton P, Simeoni S, et al. Androgen tal projections in Huntington disease. J Neuro- 33:455-456. receptor with elongated polyglutamine tract forms pathol Exp Neurol. 1999;58:165-173. 6. Hafezparast M, Klocke R, Ruhrberg C, et al. Mu- aggregates that alter axonal trafficking and mito- 36. Hurd DD, Saxton W. Kinesin mutations cause mo- tations in dynein link motor neuron degeneration chondrial distribution in motor neuronal processes. tor neuron disease phenotypes by disrupting fast to defects in retrograde transport. Science. 2003; FASEB J. 2002;16:1418-1420. axonal transport in Drosophila. Genetics. 1996; 300:808-812. 22. Li H, Li SH, Johnston H, Shelbourne PF, Li XJ. 144:1075-1085. 7. Kamal A, Stokin G, Yang Z, Xia CH, Goldstein LS. Amino-terminal fragments of mutant huntingtin 37. Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Axonal transport of amyloid precursor protein is show selective accumulation in striatal neurons and Squitieri F, Sipione S. Loss of normal huntingtin mediated by direct binding to the kinesin light chain synaptic toxicity. Nat Genet. 2000;25:385-389. function: new developments in Huntington’s dis- subunit of kinesin-I. Neuron. 2000;28:449-459. 23. Li H, Li SH, Yu ZX, Shelbourne P, Li XJ. Hunting- ease research. Trends Neurosci. 2001;24:182- 8. Gunawardena S, Goldstein LS. Disruption of axo- tin aggregate-associated axonal degeneration is 188. nal transport and neuronal viability by amyloid pre- an early pathological event in Huntington’s dis- 38. Gauthier LR, Charrin BC, Borrell-Pages M, et al. cursor protein mutations in Drosophila. Neuron. ease mice. J Neurosci. 2001;21:8473-8481. Huntingtin controls neurotrophic support and sur- 2001;32:389-401. 24. Klement IA, Skinner PJ, Kaytor MD, et al. Ataxin-1 vival of neurons by enhancing BDNF vesicular 9. Kamal A, Almenar-Queralt A, LeBlanc JF, Rob- nuclear localization and aggregation: role in poly- transport along microtubules. Cell. 2004;118: erts EA, Goldstein LS. Kinesin-mediated axonal glutamine-induced disease in SCA1 transgenic 127-138. transport of a membrane compartment contain- mice. Cell. 1998;95:41-53. 39. Szebenyi G, Morfini GA, Babcock A, et al. Neuro- ing ␤-secretase and presenilin-1 requires APP. 25. Gunawardena S, Her L, Brusch RG, et al. Disrup- pathogenic forms of huntingtin and androgen re- Nature. 2001;414:643-648. tion of axonal transport by loss of huntingtin or ceptor inhibit fast axonal transport. Neuron. 2003; 10. Takashima A, Murayama M, Muryama O, et al. expression of pathogenic polyQ proteins in 40:41-52. Presenilin 1 associates with glycogen synthase ki- Drosophila Neuron. 2003;40:1-2. 40. Yang Q, Hashizume Y, Yoshida M, et al. Morpho- nase-3␤ and its substrate tau. Proc Natl Acad Sci 26. Trushina E, Heldebrant MP, Perez-Terzic CM, et al. logical Purkinje cell changes in spinocerebellar USA. 1998;95:9637-9641. Microtubule destabilization and nuclear entry are ataxia type 6. Acta Neuropathol (Berl). 2000; 11. Pigino G, Morfini G, Pelsman A, Mattson MP, Brady sequential steps leading to toxicity in Hunting- 100:371-376. ST, Busciglio J. Alzheimer’s presenilin-1 muta- ton’s disease. Proc Natl Acad SciUSA. 2003; 41. Lee WC, Yoshihara M, Littleton JT. Cytoplasmic tions impair kinesin-based axonal transport. 100:12171-12176. aggregates trap polyglutamine-containing pro- J Neurosci. 2003;23:4499-4508. 27. Li SH, Gutekunst CA, Hersch SM, Li XJ. Interac- teins and block axonal transport in a Drosophila 12. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady tion of huntingtin-associated protein with dynac- model of Huntington’s disease. Proc Natl Acad Sci ST. Glycogen synthase kinase 3 phosphorylates tin P150Glued. J Neurosci. 1998;18:1261-1269. USA. 2004;101:3224-3229. kinesin light chains and negatively regulates ki- 28. Block-Galarza J, Chase KO, Sapp E, et al. Fast trans- 42. Bates GP, Hockly E. Experimental therapeutics in nesin-based motility. EMBO J. 2002;21:281- port and retrograde movement of huntingtin and Huntington’s disease: are models useful for thera- 293. HAP 1 in axons. Neuroreport. 1997;8:2247- peutic trials? Curr Opin Neurol. 2003;16:465- 13. Evert BO, Wullner U, Klockgether T. Cell death in 2251. 470.

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