Specialized Roles of Neurofilament Proteins in Synapses
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Brain Research Bulletin 126 (2016) 334–346 Contents lists available at ScienceDirect Brain Research Bulletin j ournal homepage: www.elsevier.com/locate/brainresbull Review Specialized roles of neurofilament proteins in synapses: Relevance to neuropsychiatric disorders a,b,∗ a,b,c,∗ Aidong Yuan , Ralph A. Nixon a Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, 10962, United States b Departments of Psychiatry, New York University School of Medicine, New York, NY, 10016, United States c Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, United States a r t i c l e i n f o a b s t r a c t Article history: Neurofilaments are uniquely complex among classes of intermediate filaments in being composed of four Received 11 July 2016 subunits (NFL, NFM, NFH and alpha-internexin in the CNS) that differ in structure, regulation, and func- Received in revised form 2 September 2016 tion. Although neurofilaments have been traditionally viewed as axonal structural components, recent Accepted 3 September 2016 evidence has revealed that distinctive assemblies of neurofilament subunits are integral components Available online 5 September 2016 of synapses, especially at postsynaptic sites. Within the synaptic compartment, the individual subunits differentially modulate neurotransmission and behavior through interactions with specific neurotrans- Keywords: mitter receptors. These newly uncovered functions suggest that alterations of neurofilament proteins Neurofilament subunit Synapse not only underlie axonopathy in various neurological disorders but also may play vital roles in cog- nition and neuropsychiatric diseases. Here, we review evidence that synaptic neurofilament proteins Dendritic spine Neuropsychiatric disease are a sizable population in the CNS and we advance the concept that changes in the levels or post- translational modification of individual NF subunits contribute to synaptic and behavioral dysfunction in certain neuropsychiatric conditions. © 2016 Elsevier Inc. All rights reserved. Contents 1. Introduction . 334 2. NF proteins in synapses . 335 2.1. Distinctive assemblies of NF subunits in synapses . 335 2.2. NF subunit-specific modulation of synaptic functions and behavior . 338 3. Alterations of NF proteins in psychiatric disorders . 339 3.1. Schizophrenia and bipolar disorder . 339 3.2. Drug addiction . 340 4. Alterations of NF proteins in Alzheimer’s disease . 341 5. Conclusion . 342 Acknowledgements . 342 References . 342 1. Introduction homopolymers, NFs in the CNS are hetero-polymers composed of Neurofilaments (NFs), the intermediate filaments of mature NFL, NFM, NFH and alpha-internexin subunits (Yuan et al., 2006). neurons, are among the most abundant proteins in brain. Unlike Although structurally distinctive, these four NF subunits share a the intermediate filaments of other cell types, which are usually basic tripartite domain structure consisting of a conserved cen- tral ␣-helical rod region, a short variable head domain at the ∗ amino-terminal end and a tail of highly variable length at the C- Corresponding authors at: Center for Dementia Research, Nathan Kline Institute, terminal end. The short head domain is rich in serine and threonine Orangeburg, New York, 10962, United States residues and contains consensus sites for O-linked glycosylation E-mail addresses: [email protected] (A. Yuan), [email protected] (R.A. Nixon). and phosphorylation (Yuan et al., 2012a). The central rod domain, http://dx.doi.org/10.1016/j.brainresbull.2016.09.002 0361-9230/© 2016 Elsevier Inc. All rights reserved. A. Yuan, R.A. Nixon / Brain Research Bulletin 126 (2016) 334–346 335 which is relatively conserved among intermediate filament family the cytoskeleton in synapses is composed of microtubules, actin members, contains long stretches of hydrophobic heptad repeats filaments, the spectrin-rich membrane skeleton, and as recently favoring formation of ␣-helical coiled-coil dimers. The C-terminal shown, NF assemblies (Yuan et al., 2015b, 2015c). Evidence is also domains contain glutamic- and lysine-rich stretches of varying emerging that the cytoskeleton, and especially the NF scaffold, acts length that mainly establish the size range (58–200 kDa on SDS as a docking platform to organize the topography of organelles gels) of the four NF subunits. Although all intermediate filament within different neuronal compartments. Rearrangements of this types serve roles as structural scaffolds, NF subunit heterogeneity topography are dynamically coordinated at least in part by cellular also confers specialized structural properties to NF, in axons where signals regulating the phosphorylation state of the binding part- the filaments are extremely long and are often arranged in paral- ners (Perrot and Julien, 2009; Rao et al., 2011; Styers et al., 2004; lel with uniform spacing conferred by the long C-terminal tails of Yuan et al., 2015b). Such evidence suggests a range of possibili- NFM and NFH extending perpendicularly from the filament core ties for understanding the newly recognized roles of individual NF (Rao et al., 2003, 2002). These unique space filling properties of NF subunits in modulating synaptic function. In this review, we con- facilitate their well-established role in caliber expansion of large- sider the properties of synaptic NF assemblies in the CNS and, in diameter myelinated axons of peripheral nerves, which is critical this context, raise the possibility that certain changes in levels or for effective nerve conduction (Zhu et al., 1997). NFs also exten- phosphorylation of NF subunits reported in neuropsychiatric dis- sively cross-link with other cytoskeletal elements along axons to orders (Table 1) disrupt synaptic signaling or, in some cases, reflect form a large metabolically stable stationary NF network (Nixon and adaptive or maladaptive responses to these synaptic disruptions. Logvinenko, 1986; Yuan et al., 2015a, 2009) that is critical to axon caliber expansion (Friede and Samorajski, 1970; Hoffman et al., 1987; Ohara et al., 1993) and organelle distribution along axons 2. NF proteins in synapses (Rao et al., 2011). Besides these unique structural and functional features, NF sub- 2.1. Distinctive assemblies of NF subunits in synapses units are distinguished from other intermediate filament proteins by the complex regulation of their head and tail domains by phos- Synapses have long been considered to be degradative sites for phorylation, especially those of NFM and NFH, which involves NF reaching terminals by axonal transport (Roots, 1983). When actions of multiple protein kinases and phosphatases at many NF proteins have been detected in synaptic fractions and bound polypeptide sites (Pant and Veeranna, 1995). Although certain to synaptic proteins in vitro, they have previously been viewed phosphorylation events are known to control tail extension and as contaminating axonal NF proteins (Matus et al., 1980) and subunit assembly and slow turnover, the purpose of such complex their possible role in synapses has rarely been entertained. Using and dynamically changing phosphate topography on NF subunits multiple independent approaches, however, Yuan et al. recently (de Waegh et al., 1992; Nixon and Sihag, 1991; Pant and Veeranna, provided definitive evidence that all four CNS NF subunits are inte- 1995) has remained puzzling, given the mainly static structural gral resident proteins of synapses and have distinct roles in synaptic support roles ascribed to NF. Both the complex hetero-polymeric function and behavior (Fig. 1)(Yuan et al., 2015b, 2015c). The NF structure and dynamically changing phosphate topography of NF assemblies isolated from synapses are distinctive as compared to proteins suggests that individual NF proteins might serve addi- those in other parts of the neuron in terms of their morphology tional biological roles although there has been relatively little and in having higher proportions of alpha-internexin, a lowered exploration of this issue until recently. phosphorylation state of NFM, and a higher NFH phosphorylations NF gene mutations are well recognized as causes of several state. This unique population of synaptic NF proteins is more abun- neurological disorders mainly involving degeneration of periph- dant in the postsynaptic area than in adjacent dendritic areas or eral nerve fibers in accordance with the prominent function of NF presynaptic terminals and exhibits a different response to subunit in supporting large-diameter myelinated axons (Brownlees et al., perturbation than the axonal population. For example, when NFM is 2002). Notably, however, NF proteins are abundant in grey matter deleted from mice, NFH phosphorylation and the ratio of NFH to NFL CNS regions as well as white matter (Chan et al., 1997) but influ- subunit increase significantly in the synaptic pool in comparison to ence caliber expansion much less dramatically in most populations the total NF pool (Yuan et al., 2015b). Because NF subunit monomers of CNS axons (Dyakin et al., 2010). These observations and evidence are inefficiently transported along axons (Yuan et al., 2003, 2006, that NF subunits can be axonally transported in various minimally 2015b), NF proteins in synapses are at least oligomeric in form and assembled forms (including as heterodimers) suggest a broader dis- can be transported as such in axons, providing one possible basis tribution and range of assembly forms of NF subunits within CNS for their synaptic location. It is also possible that some NF protein neurons,