Abstract
Neurons are extremely polarised cells in which the cytoskeleton, composed of microtubules, microfilaments and neurofilaments, plays a crucial role in maintaining structure and function. Neurofilaments, the 10-nm intermediate filaments of neurons, provide structure and mechanoresistance but also provide a scaffolding for the organization of the nucleus and organelles such as mitochondria and ER. Disruption of neurofilament organization and expression or metabolism of neurofilament proteins is characteristic of certain neurological syndromes including Amyotrophic Lateral Sclerosis, Charcot-Marie-Tooth sensorimotor neuropathies and Giant Axonal Neuropathy. Microfluorometric live imaging techniques have been instrumental in revealing the dynamics of neurofilament assembly and transport and their functions in organizing intracellular organelle networks. The insolubility of neurofilament proteins has limited identifying interactors by conventional biochemical techniques but yeast two-hybrid experiments have revealed new roles for oligomeric, nonfilamentous structures including vesicular trafficking. Although having long half-lives, new evidence points to degradation of subunits by the ubiquitin–proteasome system as a mechanism of normal turnover. Although certain E3-ligases ubiquitinating neurofilament proteins have been identified, the overall process of neurofilament degradation is not well understood. We review these mechanisms of neurofilament homeostasis and abnormalities in motor neuron and peripheral nerve disorders. Much remains to discover about the disruption of processes that leads to their pathological aggregation and accumulation and the relevance to pathogenesis. Understanding these mechanisms is crucial for identifying novel therapeutic strategies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ackerley S, Thornhill P, Grierson AJ, Brownlees J, Anderton BH, Leigh PN, Shaw CE, Miller CC (2003) Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments. J Cell Biol 161:489–495
Ackerley S, James PA, Kalli A, French S, Davies KE, Talbot K (2006) A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes. Hum Mol Genet 15:347–354
Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN (1999) Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 8:157–164
Almeida-Souza L, Goethals S, de Winter V, Dierick I, Gallardo R, Van Durme J, Irobi J, Gettemans J, Rousseau F, Schymkowitz J, Timmerman V, Janssens S (2010) Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy. J Biol Chem 285:12778–12786
Athlan ES, Mushynski WE (1997) Heterodimeric associations between neuronal intermediate filament proteins. J Biol Chem 272:31073–31078
Attali R, Warwar N, Israel A, Gurt I, McNally E, Puckelwartz M, Glick B, Nevo Y, Ben-Neriah Z, Melki J (2009) Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 18:3462–3469
Baas PW, Black MM (1990) Individual microtubules in the axon consist of domains that differ in both composition and stability. J Cell Biol 111:495–509
Baas PW, Ahmad FJ, Pienkowski TP, Brown A, Black MM (1993) Sites of microtubule stabilization for the axon. J Neurosci 13:2177–2185
Balastik M, Ferraguti F, Pires-da Silva A, Lee TH, Alvarez-Bolado G, Lu KP, Gruss P (2008) Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci U S A 105:12016–12021
Barry DM, Stevenson W, Bober BG, Wiese PJ, Dale JM, Barry GS, Byers NS, Strope JD, Chang R, Schulz DJ, Shah S, Calcutt NA, Gebremichael Y, Garcia ML (2012) Expansion of neurofilament medium C terminus increases axonal diameter independent of increases in conduction velocity or myelin thickness. J Neurosci 32:6209–6219
Bearer EL, Reese TS (1999) Association of actin filaments with axonal microtubule tracts. J Neurocytol 28:85–98
Bearer EL, Schlief ML, Breakefield XO, Schuback DE, Reese TS, LaVail JH (1999) Squid axoplasm supports the retrograde axonal transport of herpes simplex virus. Biol Bull 197:257–258
Beaulieu JM, Kriz J, Julien JP (2002) Induction of peripherin expression in subsets of brain neurons after lesion injury or cerebral ischemia. Brain Res 946:153–161
Beck R, Deek J, Jones JB, Safinya CR (2010) Gel-expanded to gel-condensed transition in neurofilament networks revealed by direct force measurements. Nat Mater 9:40–46
Bergeron C, Muntasser S, Somerville MJ, Weyer L, Percy ME (1994) Copper/zinc superoxide dismutase mRNA levels are increased in sporadic amyotrophic lateral sclerosis motorneurons. Brain Res 659:272–276
Boitard C, Villa MC, Becourt C, Gia HP, Huc C, Sempe P, Portier MM, Bach JF (1992) Peripherin: an islet antigen that is cross-reactive with nonobese diabetic mouse class II gene products. Proc Natl Acad Sci U S A 89:172–176
Bouchard JP, Barbeau A, Bouchard R, Bouchard RW (1979) Electromyography and nerve conduction studies in Friedreich’s ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Can J Neurol Sci 6:185–189
Boylan KB, Glass JD, Crook JE, Yang C, Thomas CS, Desaro P, Johnston A, Overstreet K, Kelly C, Polak M, Shaw G (2013) Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 84:467–472
Brown A (1997) Visualization of single neurofilaments by immunofluorescence microscopy of splayed axonal cytoskeletons. Cell Motil Cytoskeleton 38:133–145
Brown A, Li Y, Slaughter T, Black MM (1993) Composite microtubules of the axon: quantitative analysis of tyrosinated and acetylated tubulin along individual axonal microtubules. J Cell Sci 104(Pt 2):339–352
Brown HG, Troncoso JC, Hoh JH (1998) Neurofilament-L homopolymers are less mechanically stable than native neurofilaments. J Microsc 191:229–237
Brown A, Wang L, Jung P (2005) Stochastic simulation of neurofilament transport in axons: the “stop-and-go” hypothesis. Mol Biol Cell 16:4243–4255
Bruno C, Bertini E, Federico A, Tonoli E, Lispi ML, Cassandrini D, Pedemonte M, Santorelli FM, Filocamo M, Dotti MT, Schenone A, Malandrini A, Minetti C (2004) Clinical and molecular findings in patients with giant axonal neuropathy (GAN). Neurology 62:13–16
Burton PR, Wentz MA (1992) Neurofilaments are prominent in bullfrog olfactory axons but are rarely seen in those of the tiger salamander, Ambystoma tigrinum. J Comp Neurol 317:396–406
Carden MJ, Eagles PAM(1986) Chemical cross-linking analyses of ox neurofilaments. Biochem J 234:587–591
Carpenter S (1968) Proximal axonal enlargement in motor neuron disease. Neurology 18:841–851
Chen PC, Qin LN, Li XM, Walters BJ, Wilson JA, Mei L, Wilson SM (2009) The proteasome-associated deubiquitinating enzyme Usp14 is essential for the maintenance of synaptic ubiquitin levels and the development of neuromuscular junctions. J Neurosci: Off J Soc Neurosci 29:10909–10919
Chen H, Qian K, Du Z, Cao J, Petersen A, Liu H, Blackbourn LW 4th, Huang CL, Errigo A, Yin Y, Lu J, Ayala M, Zhang SC (2014) Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell 14:796–809
Cochard P, Paulin D (1984) Initial expression of neurofilaments and vimentin in the central and peripheral nervous system of the mouse embryo in vivo. J Neurosci 4:2080–2094
Cohlberg JA, Hajarian H, Sainte-Marie S (1987) Discrete soluble forms of middle and high molecular weight neurofilament proteins in dilute aqueous buffers. J Biol Chem 262:17009–17015
Cohlberg JA, Hajarian H, Tran T, Alipourjeddi P, Noveen A (1995) Neurofilament protein heterotetramers as assembly intermediates. J Biol Chem 270:9334–9339
Colakoglu G, Brown A (2009) Intermediate filaments exchange subunits along their length and elongate by end-to-end annealing. J Cell Biol 185:769–777
Conde C, Caceres A (2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10:319–332
Crimmins S, Jin Y, Wheeler C, Huffman AK, Chapman C, Dobrunz LE, Levey A, Roth KA, Wilson JA, Wilson SM (2006) Transgenic rescue of ataxia mice with neuronal-specific expression of ubiquitin-specific protease 14. J Neurosci 26:11423–11431
Dale JM, Garcia ML (2012) Neurofilament phosphorylation during development and disease: which came first, the phosphorylation or the accumulation? J Amino Acids 2012:382107
Deloulme JC, Gentil BJ, Baudier J (2003) Monitoring of S100 homodimerization and heterodimeric interactions by the yeast two-hybrid system. Microsc Res Tech 60:560–568
Doroudchi MM, Durham HD (1996) Activation of protein kinase C induces neurofilament fragmentation, hyperphosphorylation of perikaryal neurofilaments and proximal dendritic swellings in cultured motor neurons. J Neuropathol Exp Neurol 55:246–256
Durant S, Geutskens S, Van Blokland SC, Coulaud J, Alves V, Pleau JM, Versnel M, Drexhage HA, Homo-Delarche F (2003) Proapoptosis and antiapoptosis-related molecules during postnatal pancreas development in control and nonobese diabetic mice: relationship with innervation. Lab Investig 83:227–239
Durham HD, Roy J, Dong L, Figlewicz DA (1997) Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol 56:523–530
Ehlers MD, Fung ET, O’Brien RJ, Huganir RL (1998) Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J Neurosci 18:720–730
Elder GA, Friedrich VL Jr, Bosco P, Kang C, Gourov A, Tu PH, Lee VM, Lazzarini RA (1998a) Absence of the mid-sized neurofilament subunit decreases axonal calibers, levels of light neurofilament (NF-L), and neurofilament content. J Cell Biol 141:727–739
Elder GA, Friedrich VL Jr, Kang C, Bosco P, Gourov A, Tu PH, Zhang B, Lee VM, Lazzarini RA (1998b) Requirement of heavy neurofilament subunit in the development of axons with large calibers. J Cell Biol 143:195–205
Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melancon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A (2000) ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24:120–125
Escurat M, Djabali K, Gumpel M, Gros F, Portier MM (1990) Differential expression of two neuronal intermediate-filament proteins, peripherin and the low-molecular-mass neurofilament protein (NF-L), during the development of the rat. J Neurosci 10:764–784
Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36:602–606
Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, Rizzuto N (2004) Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology 62:1429–1431
Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G, Bertolasi L, Rizzuto N (2007) Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain 130:394–403
Fernyhough P, Gallagher A, Averill SA, Priestley JV, Hounsom L, Patel J, Tomlinson DR (1999) Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes 48:881–889
Fifkova E, Delay RJ (1982) Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity. J Cell Biol 95:345–350
Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP (1994) Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 3:1757–1761
Foisner R, Leichtfried FE, Herrmann H, Small JV, Lawson D, Wiche G (1988) Cytoskeleton-associated plectin: in situ localization, in vitro reconstitution, and binding to immobilized intermediate filament proteins. J Cell Biol 106:723–733
Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, Bestwick JP, Monsch AU, Regeniter A, Lindberg RL, Kappos L, Leppert D, Petzold A, Giovannoni G, Kuhle J (2013) Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS ONE 8:e75091
Garcia ML, Lobsiger CS, Shah SB, Deerinck TJ, Crum J, Young D, Ward CM, Crawford TO, Gotow T, Uchiyama Y, Ellisman MH, Calcutt NA, Cleveland DW (2003) NF-M is an essential target for the myelin-directed “outside-in” signaling cascade that mediates radial axonal growth. J Cell Biol 163:1011–1020
Garcia ML, Rao MV, Fujimoto J, Garcia VB, Shah SB, Crum J, Gotow T, Uchiyama Y, Ellisman M, Calcutt NA, Cleveland DW (2009) Phosphorylation of highly conserved neurofilament medium KSP repeats is not required for myelin-dependent radial axonal growth. J Neurosci 29:1277–1284
Gelber C, Paborsky L, Singer S, McAteer D, Tisch R, Jolicoeur C, Buelow R, McDevitt H, Fathman CG (1994) Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes. Diabetes 43:33–39
Gentil BJ, Minotti S, Beange M, Baloh RH, Julien JP, Durham HD (2011) Normal role of the low-molecular-weight neurofilament protein in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease. FASEB J 26:1194–1203
Gentil BJ, Mushynski WE, Durham HD (2013) Heterogeneity in the properties of NEFL mutants causing Charcot-Marie-Tooth disease results in differential effects on neurofilament assembly and susceptibility to intervention by the chaperone-inducer, celastrol. Int J Biochem Cell Biol 45:1499–1508
Gentil BJ, McLean JR, Xiao S, Zhao B, Durham HD, Robertson J (2014) A two-hybrid screen identifies an unconventional role for the intermediate filament peripherin in regulating the subcellular distribution of the SNAP25 interacting protein, SIP30. J Neurochem 131(5):588–601
Giasson BI, Mushynski WE (1996) Aberrant stress-induced phosphorylation of perikaryal neurofilaments. J Biol Chem 271:30404–30409
Giasson BI, Mushynski WE (1998) Intermediate filament disassembly in cultured dorsal root ganglion neurons is associated with amino-terminal head domain phosphorylation of specific subunits. J Neurochem 70:1869–1875
Giasson BI, Cromlish JA, Athlan ES, Mushynski WE (1996) Activation of cyclic AMP-dependent protein kinase in okadaic acid-treated neurons potentiates neurofilament fragmentation and stimulates phosphorylation of Ser2 in the low-molecular-mass neurofilament subunit. J Neurochem 66:1207–1213
Gibb BJ, Robertson J, Miller CC (1996) Assembly properties of neurofilament light chain Ser55 mutants in transfected mammalian cells. J Neurochem 66:1306–1311
Gibb BJ, Brion JP, Brownlees J, Anderton BH, Miller CC (1998) Neuropathological abnormalities in transgenic mice harbouring a phosphorylation mutant neurofilament transgene. J Neurochem 70:492–500
Gros-Louis F, Lariviere R, Gowing G, Laurent S, Camu W, Bouchard JP, Meininger V, Rouleau GA, Julien JP (2004) A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J Biol Chem 279:45951–45956
Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE (2001) A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29:166–173
Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R Jr, Chen A, Hornstein E (2010) miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 107:13111–13116
Hatzfeld M, Weber K (1990) The coiled coil of in vitro assembled keratin filaments is a heterodimer of type I and II keratins: use of site-specific mutagenesis and recombinant protein expression. J Cell Biol 110:1199–1210
Haynes RL, Borenstein NS, Desilva TM, Folkerth RD, Liu LG, Volpe JJ, Kinney HC (2005) Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol 484:156–167
Herrmann H, Aebi U (2000) Intermediate filaments and their associates: multi-talented structural elements specifying cyto architecture and cytodynamics. Curr Opin Cell Biol 12:79–90
Herrmann H, Haner M, Brettel M, Ku NO, Aebi U (1999) Characterization of distinct early assembly units of different intermediate filament proteins. J Mol Biol 286:1403–1420
Hoffman PN, Lasek RJ (1975) The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons. J Cell Biol 66:351–366
Holmgren A, Bouhy D, De Winter V, Asselbergh B, Timmermans JP, Irobi J, Timmerman V (2013) Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments. Acta Neuropathol 126:93–108
Ishihara T, Higuchi M, Zhang B, Yoshiyama Y, Hong M, Trojanowski JQ, Lee VM (2001) Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J Neurosci 21:6026–6035
Ishtiaq M, Campos-Melo D, Volkening K, Strong MJ (2014) Analysis of novel NEFL mRNA targeting microRNAs in amyotrophic lateral sclerosis. PLoS ONE 9:e85653
Itoh T, Sobue G, Ken E, Mitsuma T, Takahashi A, Trojanowski JQ (1992) Phosphorylated high molecular weight neurofilament protein in the peripheral motor, sensory and sympathetic neuronal perikarya: system-dependent normal variations and changes in amyotrophic lateral sclerosis and multiple system atrophy. Acta Neuropathol 83:240–245
Jacomy H, Zhu Q, Couillard-Despres S, Beaulieu JM, Julien JP (1999) Disruption of type IV intermediate filament network in mice lacking the neurofilament medium and heavy subunits. J Neurochem 73:972–984
Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos S, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V (2003) Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126:590–597
Kabzinska D, Perez-Olle R, Goryunov D, Drac H, Ryniewicz B, Hausmanowa-Petrusewicz I, Kochanski A, Liem RK (2006) Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? functional analysis using cell culture models. J Peripher Nerv Syst 11:225–231
Kapitein LC, Hoogenraad CC (2011) Which way to go? Cytoskeletal organization and polarized transport in neurons. Mol Cell Neurosci 46:9–20
Kaplan MP, Chin SS, Fliegner KH, Liem RK (1990) Alpha-internexin, a novel neuronal intermediate filament protein, precedes the low molecular weight neurofilament protein (NF-L) in the developing rat brain. J Neurosci 10:2735–2748
Karpati G, Carpenter S, Durham H (1988) A hypothesis for the pathogenesis of amyotrophic lateral sclerosis. Rev Neurol 144:672–675
Karpova A, Mikhaylova M, Bera S, Bar J, Reddy PP, Behnisch T, Rankovic V, Spilker C, Bethge P, Sahin J, Kaushik R, Zuschratter W, Kahne T, Naumann M, Gundelfinger ED, Kreutz MR (2013) Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. Cell 152:1119–1133
Kong J, Tung VW, Aghajanian J, Xu Z (1998) Antagonistic roles of neurofilament subunits NF-H and NF-M against NF-L in shaping dendritic arborization in spinal motor neurons. J Cell Biol 140:1167–1176
Koutras C, Levesque G (2011) Identification of novel NPRAP/delta-catenin-interacting proteins and the direct association of NPRAP with dynamin 2. PLoS ONE 6:e25379
Kreplak L, Bar H, Leterrier JF, Herrmann H, Aebi U (2005) Exploring the mechanical behavior of single intermediate filaments. J Mol Biol 354:569–577
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208
Lariviere RC, Nguyen MD, Ribeiro-da-Silva A, Julien JP (2002) Reduced number of unmyelinated sensory axons in peripherin null mice. J Neurochem 81:525–532
Lariviere R, Gaudet R, Gentil BJ, Girard M, Conte TC, Minotti S, Leclerc-Desaulniers K, Gehring K, McKinney RA, Shoubridge EA, McPherson PS, Durham HD, Brais B (2014) Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay. Hum Mol Genet
Lasek RJ, Paggi P, Katz MJ (1992) Slow axonal transport mechanisms move neurofilaments relentlessly in mouse optic axons. J Cell Biol 117:607–616
Leblond CS, Kaneb HM, Dion PA, Rouleau GA (2014) Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp Neurol. doi:10.1016/j.expneurol.2014.04.013
Leung CL, Liem RK (1996) Characterization of interactions between the neurofilament triplet proteins by the yeast two-hybrid system. J Biol Chem 271:14041–14044
Levavasseur F, Zhu Q, Julien JP (1999) No requirement of alpha-internexin for nervous system development and for radial growth of axons. Brain Res Mol Brain Res 69:104–112
Liem RK, Hutchison SB (1982) Purification of individual components of the neurofilament triplet: filament assembly from the 70 000-dalton subunit. Biochemistry 21:3221–3226
Ligon LA, Steward O (2000a) Movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol 427:340–350
Ligon LA, Steward O (2000b) Role of microtubules and actin filaments in the movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol 427:351–361
Liu Y, Staal JA, Canty AJ, Kirkcaldie MT, King AE, Bibari O, Mitew ST, Dickson TC, Vickers JC (2013) Cytoskeletal changes during development and aging in the cortex of neurofilament light protein knockout mice. J Comp Neurol 521:1817–1827
Macioce P, Gandolfi N, Leung CL, Chin SS, Malchiodi-Albedi F, Ceccarini M, Petrucci TC, Liem RK (1999) Characterization of NF-L and betaIISigma1-spectrin interaction in live cells. Exp Cell Res 250:142–154
Mahammad S, Murthy SN, Didonna A, Grin B, Israeli E, Perrot R, Bomont P, Julien JP, Kuczmarski E, Opal P, Goldman RD (2013) Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J Clin Invest 123:1964–1975
Manser C, Stevenson A, Banner S, Davies J, Tudor EL, Ono Y, Leigh PN, McLoughlin DM, Shaw CE, Miller CC (2008) Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport. FEBS Lett 582:2303–2308
Markham JA, Fifkova E (1986) Actin filament organization within dendrites and dendritic spines during development. Brain Res 392:263–269
Mellad JA, Warren DT, Shanahan CM (2011) Nesprins LINC the nucleus and cytoskeleton. Curr Opin Cell Biol 23:47–54
Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV (2000) A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet 67:37–46
Mialki RK, Zhao J, Wei J, Mallampalli DF, Zhao Y (2013) Overexpression of USP14 protease reduces I-kappaB protein levels and increases cytokine release in lung epithelial cells. J Biol Chem 288:15437–15441
Millecamps S, Julien JP (2004) [35S]Methionine metabolic labeling to study axonal transport of neuronal intermediate filament proteins in vivo. Methods Cell Biol 78:555–571
Millecamps S, Gowing G, Corti O, Mallet J, Julien JP (2007) Conditional NF-L transgene expression in mice for in vivo analysis of turnover and transport rate of neurofilaments. J Neurosci 27:4947–4956
Miltenberger-Miltenyi G, Janecke AR, Wanschitz JV, Timmerman V, Windpassinger C, Auer-Grumbach M, Loscher WN (2007) Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Arch Neurol 64:966–970
Mironov SL (2006) Spontaneous and evoked neuronal activities regulate movements of single neuronal mitochondria. Synapse 59:403–411
Mironov SL, Symonchuk N (2006) ER vesicles and mitochondria move and communicate at synapses. J Cell Sci 119:4926–4934
Morgan JT, Pfeiffer ER, Thirkill TL, Kumar P, Peng G, Fridolfsson HN, Douglas GC, Starr DA, Barakat AI (2011) Nesprin-3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow-induced polarization. Mol Biol Cell 22:4324–4334
Nakamura Y, Hashimoto R, Kashiwagi Y, Aimoto S, Fukusho E, Matsumoto N, Kudo T, Takeda M (2000) Major phosphorylation site (Ser55) of neurofilament L by cyclic AMP-dependent protein kinase in rat primary neuronal culture. J Neurochem 74:949–959
Nakano I, Hirano A (1987) Atrophic cell processes of large motor neurons in the anterior horn in amyotrophic lateral sclerosis: observation with silver impregnation method. J Neuropathol Exp Neurol 46:40–49
Nixon RA, Logvinenko KB (1986) Multiple fates of newly synthesized neurofilament proteins: evidence for a stationary neurofilament network distributed nonuniformly along axons of retinal ganglion cell neurons. J Cell Biol 102:647–659
Pant HC (1988) Dephosphorylation of neurofilament proteins enhances their susceptibility to degradation by calpain. Biochem J 256:665–668
Perez-Olle R, Leung CL, Liem RK (2002) Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation. J Cell Sci 115:4937–4946
Perez-Olle R, Jones ST, Liem RK (2004) Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet 13:2207–2220
Peth A, Kukushkin N, Bosse M, Goldberg AL (2013) Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs. J Biolo Chem 288:7781–7790
Pleau JM, Marche PN, Serrano MP, Boitard C, Bach JF (1993) Evidence for antigen driven selection in two monoclonal auto-antibodies derived from nonobese diabetic mice. Mol Immunol 30:1257–1264
Puertas MC, Carrillo J, Pastor X, Ampudia RM, Planas R, Alba A, Bruno R, Pujol-Borrell R, Estanyol JM, Vives-Pi M, Verdaguer J (2007) Peripherin is a relevant neuroendocrine autoantigen recognized by islet-infiltrating B lymphocytes. J Immunol 178:6533–6539
Rao MV, Engle LJ, Mohan PS, Yuan A, Qiu D, Cataldo A, Hassinger L, Jacobsen S, Lee VM, Andreadis A, Julien JP, Bridgman PC, Nixon RA (2002a) Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density. J Cell Biol 159:279–290
Rao MV, Garcia ML, Miyazaki Y, Gotow T, Yuan A, Mattina S, Ward CM, Calcutt NA, Uchiyama Y, Nixon RA, Cleveland DW (2002b) Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport. J Cell Biol 158:681–693
Rao MV, Campbell J, Yuan A, Kumar A, Gotow T, Uchiyama Y, Nixon RA (2003) The neurofilament middle molecular mass subunit carboxyl-terminal tail domains is essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate. J Cell Biol 163:1021–1031
Rao MV, Mohan PS, Kumar A, Yuan A, Montagna L, Campbell J, Veeranna EEM, Julien JP, Nixon RA (2011) The myosin Va head domain binds to the neurofilament-L rod and modulates endoplasmic reticulum (ER) content and distribution within axons. PLoS ONE 6:e17087
Robertson J, Doroudchi MM, Nguyen MD, Durham HD, Strong MJ, Shaw G, Julien JP, Mushynski WE (2003) A neurotoxic peripherin splice variant in a mouse model of ALS. J Cell Biol 160:939–949
Schmidt RE, Beaudet LN, Plurad SB, Dorsey DA (1997a) Axonal cytoskeletal pathology in aged and diabetic human sympathetic autonomic ganglia. Brain Res 769:375–383
Schmidt RE, Dorsey D, Parvin CA, Beaudet LN, Plurad SB, Roth KA (1997b) Dystrophic axonal swellings develop as a function of age and diabetes in human dorsal root ganglia. J Neuropathol Exp Neurol 56:1028–1043
Scott D, Smith KE, O’Brien BJ, Angelides KJ (1985) Characterization of mammalian neurofilament triplet proteins. Subunit stoichiometry and morphology of native and reconstituted filaments. J Biol Chem 260:10736–10747
Sihag RK, Nixon RA (1989) In vivo phosphorylation of distinct domains of the 70-kilodalton neurofilament subunit involves different protein kinases. J Biol Chem 264:457–464
Sihag RK, Nixon RA (1990) Phosphorylation of the amino-terminal head domain of the middle molecular mass 145-kDa subunit of neurofilaments. Evidence for regulation by second messenger-dependent protein kinases. J Biol Chem 265:4166–4171
Sihag RK, Nixon RA (1991) Identification of Ser-55 as a major protein kinase A phosphorylation site on the 70-kDa subunit of neurofilaments. Early turnover during axonal transport. J Biol Chem 266:18861–18867
Sihag RK, Jeng AY, Nixon RA (1988) Phosphorylation of neurofilament proteins by protein kinase C. FEBS Lett 233:181–185
Sihag RK, Jaffe H, Nixon RA, Rong X (1999) Serine-23 is a major protein kinase A phosphorylation site on the amino-terminal head domain of the middle molecular mass subunit of neurofilament proteins. J Neurochem 72:491–499
Sobue G, Hashizume Y, Yasuda T, Mukai E, Kumagai T, Mitsuma T, Trojanowski JQ (1990) Phosphorylated high molecular weight neurofilament protein in lower motor neurons in amyotrophic lateral sclerosis and other neurodegenerative diseases involving ventral horn cells. Acta Neuropathol 79:402–408
Steinert PM (1990) The two-chain coiled-coil molecule of native epidermal keratin intermediate filaments is a type I-type II heterodimer. J Biol Chem 265:8766–8774
Takeda T, Uchihara T, Nakayama Y, Nakamura A, Sasaki S, Kakei S, Uchiyama S, Duyckaerts C, Yoshida M (2014) Dendritic retraction, but not atrophy, is consistent in amyotrophic lateral sclerosis-comparison between Onuf’s neurons and other sacral motor neurons. Acta Neuropathol Commun 2:11
Tradewell ML, Durham HD, Mushynski WE, Gentil BJ (2009) Mitochondrial and axonal abnormalities precede disruption of the neurofilament network in a model of Charcot-Marie-Tooth disease type 2E and are prevented by heat shock proteins in a mutant-specific fashion. J Neuropathol Exp Neurol 68:642–652
Trivedi N, Jung P, Brown A (2007) Neurofilaments switch between distinct mobile and stationary states during their transport along axons. J Neurosci 27:507–516
Troy CM, Muma NA, Greene LA, Price DL, Shelanski ML (1990) Regulation of peripherin and neurofilament expression in regenerating rat motor neurons. Brain Res 529:232–238
Uchida A, Alami NH, Brown A (2009) Tight functional coupling of kinesin-1A and dynein motors in the bidirectional transport of neurofilaments. Mol Biol Cell 20:4997–5006
Uchida A, Colakoglu G, Wang L, Monsma PC, Brown A (2013) Severing and end-to-end annealing of neurofilaments in neurons. Proc Natl Acad Sci U S A 110:E2696–2705
Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211
Volkening K, Leystra-Lantz C, Yang W, Jaffee H, Strong MJ (2009) Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res 1305:168–182
Wang Q, Song F, Zhang C, Zhao X, Zhu Z, Yu S, Xie K (2011) Carboxyl-terminus of Hsc70 interacting protein mediates 2,5-hexanedione-induced neurofilament medium chain degradation. Biochem Pharmacol 81:793–799
Wiche G, Winter L (2011) Plectin isoforms as organizers of intermediate filament cytoarchitecture. Biogeosciences 1:14–20
Wickert U, Mucke N, Wedig T, Muller SA, Aebi U, Herrmann H (2005) Characterization of the in vitro co-assembly process of the intermediate filament proteins vimentin and desmin: mixed polymers at all stages of assembly. Eur J Cell Biol 84:379–391
Wuerker RB, Palay SL (1969) Neurofilaments and microtubules in anterior horn cells of the rat. Tissue Cell 1:387–402
Xiao S, Tjostheim S, Sanelli T, McLean JR, Horne P, Fan Y, Ravits J, Strong MJ, Robertson J (2008) An aggregate-inducing peripherin isoform generated through intron retention is upregulated in amyotrophic lateral sclerosis and associated with disease pathology. J Neurosci 28:1833–1840
Yabe JT, Pimenta A, Shea TB (1999) Kinesin-mediated transport of neurofilament protein oligomers in growing axons. J Cell Sci 112(Pt 21):3799–3814
Yagihashi S, Kamijo M, Watanabe K (1990) Reduced myelinated fiber size correlates with loss of axonal neurofilaments in peripheral nerve of chronically streptozotocin diabetic rats. Am J Pathol 136:1365–1373
Yates DM, Manser C, De Vos KJ, Shaw CE, McLoughlin DM, Miller CC (2009) Neurofilament subunit (NFL) head domain phosphorylation regulates axonal transport of neurofilaments. Eur J Cell Biol 88:193–202
Ylikallio E, Poyhonen R, Zimon M, De Vriendt E, Hilander T, Paetau A, Jordanova A, Lonnqvist T, Tyynismaa H (2013) Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum Mol Genet 22:2975–2983
Yoshihara T, Yamamoto M, Hattori N, Misu K, Mori K, Koike H, Sobue G (2002) Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. J Peripher Nerv Syst 7:221–224
Yuan A, Rao MV, Kumar A, Julien JP, Nixon RA (2003) Neurofilament transport in vivo minimally requires hetero-oligomer formation. J Neurosci 23:9452–9458
Yuan A, Nixon RA, Rao MV (2006a) Deleting the phosphorylated tail domain of the neurofilament heavy subunit does not alter neurofilament transport rate in vivo. Neurosci Lett 393:264–268
Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna LRK, Eyer J, Peterson AC, Julien JP, Nixon RA (2006b) Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci 26:10006–10019
Yuan A, Sasaki T, Kumar A, Peterhoff CM, Rao MV, Liem RK, Julien JP, Nixon RA (2012) Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons. J Neurosci 32:8501–8508
Yum SW, Zhang J, Mo K, Li J, Scherer SS (2009) A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol 66:759–770
Zackroff RV, Idler WW, Steinert PM, Goldman RD (1982) In vitro reconstitution of intermediate filaments form mammalian neurofilament triplet polypeptides. Proc Natl Acad Sci U S A 79:754–757
Zhai J, Lin H, Julien JP, Schlaepfer WW (2007) Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum Mol Genet 16:3103–3116
Zhang Z, Casey DM, Julien JP, Xu Z (2002) Normal dendritic arborization in spinal motoneurons requires neurofilament subunit L. J Comp Neurol 450:144–152
Zhu Q, Couillard-Despres S, Julien JP (1997) Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol 148:299–316
Zuchner S, Vorgerd M, Sindern E, Schroder JM (2004) The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord 14:147–157
Acknowledgments
We thank Sandra Minotti for her precious help in preparing spinal cord and dorsal root ganglia cultures and Patrick Bouchard for confocal microscopy. This work is supported by a grant from the ARSACS Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gentil, B.J., Tibshirani, M. & Durham, H.D. Neurofilament dynamics and involvement in neurological disorders. Cell Tissue Res 360, 609–620 (2015). https://doi.org/10.1007/s00441-014-2082-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-014-2082-7