Cytoskeletal changes in diseases of the nervous system

Abstract

The neuronal cytoskeleton not only provides the structural backbone of neurons, but also plays a fundamental role in maintaining neuronal functions. Dysregulation of neuronal architecture is evident in both injury and diseases of the central nervous system. These changes often result in the disruption of protein trafficking, loss of synapses and the death of neurons, ultimately impacting on signal transmission and manifesting in the disease phenotype. Furthermore, mutations in cytoskeletal proteins have been implicated in numerous diseases and, in some cases, identified as the cause of the disease, highlighting the critical role of the cytoskeleton in disease pathology. This review focuses on the role of cytoskeletal proteins in the pathology of mental disorders, neurodegenerative diseases and motor function deficits. In particular, we illustrate how cytoskeletal proteins can be directly linked to disease pathology and progression.

Keywords

cytoskeleton / actin / microtubules / intermediate filaments / nervous system / disease

References

[1] Al-ChalabiA, AndersenP M, NilssonP, ChiozaB, AnderssonJ L, RussC, ShawC E, PowellJ F, LeighP N (1999). Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet, 8(2): 157–164

[2] AndersonS A, VolkD W, LewisD A (1996). Increased density of microtubule associated protein 2-immunoreactive neurons in the prefrontal white matter of schizophrenic subjects. Schizophr Res, 19(2–3): 111–119

[3] AndrianantoandroE, PollardT D (2006). Mechanism of actin filament turnover by severing and nucleation at different concentrations of ADF/cofilin. Mol Cell, 24(1): 13–23

[4] AndrieuxA, SalinP A, VernetM, KujalaP, BaratierJ, Gory-FauréS, BoscC, PointuH, ProiettoD, SchweitzerA, DenarierE, KlumpermanJ, JobD (2002). The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders. Genes Dev, 16(18): 2350–2364

[5] ArberS, BarbayannisF A, HanserH, SchneiderC, StanyonC A, BernardO, CaroniP (1998). Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature, 393(6687): 805–809

[6] ArmstrongR A, CairnsN J (2012). Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease: a comparative study of eight disorders. J Neural Transm, 119(12): 1551–1560

[7] ArmstrongR A, KertyE, SkullerudK, CairnsN J (2006). Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID): a study using alpha-internexin immunohistochemistry and principal components analysis (PCA). J Neural Transm, 113(9): 1207–1215

[8] AsburyA K, GaleM K, CoxS C, BaringerJ R, BergB O (1972). Giant axonal neuropathy—a unique case with segmental neurofilamentous masses. Acta Neuropathol, 20(3): 237–247

[9] AsrarS, MengY, ZhouZ, TodorovskiZ, HuangW W, JiaZ (2009). Regulation of hippocampal long-term potentiation by p21-activated protein kinase 1 (PAK1). Neuropharmacology, 56(1): 73–80

[10] BaasP W, AhmadF J (2013). Beyond taxol: microtubule-based treatment of disease and injury of the nervous system. Brain, 136(Pt 10): 2937–2951

[11] BallatoreC, LeeV M, TrojanowskiJ Q (2007). Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci, 8(9): 663–672

[12] BégouM, BrunP, BertrandJ B, JobD, SchweitzerA, D’AmatoT, SaoudM, AndrieuxA, Suaud-ChagnyM F (2007). Post-pubertal emergence of alterations in locomotor activity in stop null mice. Synapse, 61(9): 689–697

[13] BégouM, VolleJ, BertrandJ B, BrunP, JobD, SchweitzerA, SaoudM, D’AmatoT, AndrieuxA, Suaud-ChagnyM F (2008). The stop null mice model for schizophrenia displays [corrected] cognitive and social deficits partly alleviated by neuroleptics. Neuroscience, 157(1): 29–39

[14] BelichenkoP V, DahlströmA (1995). Studies on the 3-dimensional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and Lucifer yellow microinjections. J Neurosci Methods, 57(1): 55–61

[15] Bento-AbreuA, Van DammeP, Van Den BoschL, RobberechtW (2010). The neurobiology of amyotrophic lateral sclerosis. Eur J Neurosci, 31(12): 2247–2265

[16] BergeronC, Beric-MaskarelK, MuntasserS, WeyerL, SomervilleM J, PercyM E (1994). Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons. J Neuropathol Exp Neurol, 53(3): 221–230

[17] BernhardtR, MatusA (1984). Light and electron microscopic studies of the distribution of microtubule-associated protein 2 in rat brain: a difference between dendritic and axonal cytoskeletons. J Comp Neurol, 226(2): 203–221

[18] BishopA L, HallA (2000). Rho GTPases and their effector proteins. Biochem J, 348(Pt 2): 241–255

[19] BloomG S, ValleeR B (1983). Association of microtubule-associated protein 2 (MAP 2) with microtubules and intermediate filaments in cultured brain cells. J Cell Biol, 96(6): 1523–1531

[20] BocquetA, BergesR, FrankR, RobertP, PetersonA C, EyerJ (2009). Neurofilaments bind tubulin and modulate its polymerization. J Neurosci, 29(35): 11043–11054

[21] BoschM, HayashiY (2012). Structural plasticity of dendritic spines. Curr Opin Neurobiol, 22(3): 383–388

[22] BrettschneiderJ, PetzoldA, SüssmuthS D, LudolphA C, TumaniH (2006). Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology, 66(6): 852–856

[23] BrunP, BégouM, AndrieuxA, Mouly-BadinaL, ClergetM, SchweitzerA, ScarnaH, RenaudB, JobD, Suaud-ChagnyM F (2005). Dopaminergic transmission in STOP null mice. J Neurochem, 94(1): 63–73

[24] BrundenK R, ZhangB, CarrollJ, YaoY, PotuzakJ S, HoganA M, IbaM, JamesM J, XieS X, BallatoreC, SmithA B 3rd, LeeV M Y, TrojanowskiJ Q (2010). Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci, 30(41): 13861–13866

[25] BugyiB, PappG, HildG, LõrinczyD, NevalainenE M, LappalainenP, SomogyiB, NyitraiM (2006). Formins regulate actin filament flexibility through long range allosteric interactions. J Biol Chem, 281(16): 10727–10736

[26] CaceresA, BankerG, StewardO, BinderL, PayneM (1984). MAP2 is localized to the dendrites of hippocampal neurons which develop in culture. Brain Res, 315(2): 314–318

[27] CairnsN J, LeeV M Y, TrojanowskiJ Q (2004). The cytoskeleton in neurodegenerative diseases. J Pathol, 204(4): 438–449

[28] ChaiX, FörsterE, ZhaoS, BockH H, FrotscherM (2009). Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci, 29(1): 288–299

[29] ChenY, ZhengZZ, HuangR, ChenK, SongW, ZhaoB, ChenX, YangY, YuanL, ShangHF (2013) PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis. Neurobiol Aging34:1922 e1921–1925.

[30] ClintonS M, AbelsonS, HaroutunianV, DavisK, Meador-WoodruffJ H (2004). Neurofilament subunit protein abnormalities in the thalamus in scizophrenia. Thalamus Relat Syst, 2: 265–272

[31] ClintonS M, HaroutunianV, DavisK L, Meador-WoodruffJ H (2003). Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am J Psychiatry, 160(6): 1100–1109

[32] CohenR S, ChungS K, PfaffD W (1985). Immunocytochemical localization of actin in dendritic spines of the cerebral cortex using colloidal gold as a probe. Cell Mol Neurobiol, 5(3): 271–284

[33] CollardJ F, CôtéF, JulienJ P (1995). Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature, 375(6526): 61–64

[34] CôtéF, CollardJ F, JulienJ P (1993). Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell, 73(1): 35–46

[35] CotterD, WilsonS, RobertsE, KerwinR, EverallI P (2000). Increased dendritic MAP2 expression in the hippocampus in schizophrenia. Schizophr Res, 41(2): 313–323

[36] DaoudH, DobrzenieckaS, CamuW, MeiningerV, DupreN, DionPA, RouleauGA (2013) Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients. Neurobiol Aging34:1311 e1311–1312.

[37] DehmeltL, HalpainS (2004). Actin and microtubules in neurite initiation: are MAPs the missing link? J Neurobiol, 58(1): 18–33

[38] DentE W, KalilK (2001). Axon branching requires interactions between dynamic microtubules and actin filaments. J Neurosci, 21(24): 9757–9769

[39] DeoA J, GoldszerI M, LiS, DiBitettoJ V, HenteleffR, SampsonA, LewisD A, PenzesP, SweetR A (2013). PAK1 protein expression in the auditory cortex of schizophrenia subjects. PLoS ONE, 8(4): e59458

[40] Díez-GuerraF J, AvilaJ (1993). MAP2 phosphorylation parallels dendrite arborization in hippocampal neurones in culture. Neuroreport, 4(4): 419–422

[41] DiProsperoN A, ChenE Y, CharlesV, PlomannM, KordowerJ H, TagleD A (2004). Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol, 33(5): 517–533

[42] DixitR, RossJ L, GoldmanY E, HolzbaurE L (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science, 319(5866): 1086–1089

[43] DomR, MalfroidM, BaroF (1976). Neuropathology of Huntington’s chorea.Studies of the ventrobasal complex of the thalamus. Neurology, 26(1): 64–68

[44] DowningK H, NogalesE (1998). Tubulin and microtubule structure. Curr Opin Cell Biol, 10(1): 16–22

[45] DuanW, GuoY, JiangH, YuX, LiC (2011). MG132 enhances neurite outgrowth in neurons overexpressing mutant TAR DNA-binding protein-43 via increase of HO-1. Brain Res, 1397: 1–9

[46] EbnethA, GodemannR, StamerK, IllenbergerS, TrinczekB, MandelkowE (1998). Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol, 143(3): 777–794

[47] EdwardsD C, SandersL C, BokochG M, GillG N (1999). Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol, 1(5): 253–259

[48] EhlersM D, FungE T, O’BrienR J, HuganirR L (1998). Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J Neurosci, 18(2): 720–730

[49] EhlersM D, TingleyW G, HuganirR L (1995). Regulated subcellular distribution of the NR1 subunit of the NMDA receptor. Science, 269(5231): 1734–1737

[50] FerriC P, PrinceM, BrayneC, BrodatyH, FratiglioniL, GanguliM, HallK, HasegawaK, HendrieH, HuangY, JormA, MathersC, MenezesP R, RimmerE, ScazufcaM, and the Alzheimer’s Disease International (2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 366(9503): 2112–2117

[51] FiglewiczD A, KrizusA, MartinoliM G, MeiningerV, DibM, RouleauG A, JulienJ P (1994). Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet, 3(10): 1757–1761

[52] FreimanT M, Eismann-SchweimlerJ, FrotscherM (2011). Granule cell dispersion in temporal lobe epilepsy is associated with changes in dendritic orientation and spine distribution. Exp Neurol, 229(2): 332–338

[53] FuchsE, ClevelandD W (1998). A structural scaffolding of intermediate filaments in health and disease. Science, 279(5350): 514–519

[54] FulgaT A, Elson-SchwabI, KhuranaV, SteinhilbM L, SpiresT L, HymanB T, FeanyM B (2007). Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol, 9(2): 139–148

[55] GallowayP G, MulvihillP, PerryG (1992). Filaments of Lewy bodies contain insoluble cytoskeletal elements. Am J Pathol, 140(4): 809–822

[56] GallowayP G, PerryG, GambettiP (1987). Hirano body filaments contain actin and actin-associated proteins. J Neuropathol Exp Neurol, 46(2): 185–199

[57] GareyL J, OngW Y, PatelT S, KananiM, DavisA, MortimerA M, BarnesT R, HirschS R (1998). Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry, 65(4): 446–453

[58] GeW W, WenW, StrongW, Leystra-LantzC, StrongM J (2005). Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA. J Biol Chem, 280(1): 118–124

[59] GibsonP H, TomlinsonB E (1977). Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci, 33(1–2): 199–206

[60] GlantzL A, LewisD A (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry, 57(1): 65–73

[61] GlantzL A, LewisD A (2001). Dendritic spine density in schizophrenia and depression. Arch Gen Psychiatry, 58(2): 203

[62] GoedertM, WischikC M, CrowtherR A, WalkerJ E, KlugA (1988). Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA, 85(11): 4051–4055

[63] Grundke-IqbalI, IqbalK, QuinlanM, TungY C, ZaidiM S, WisniewskiH M (1986a). Microtubule-associated protein tau.A component of Alzheimer paired helical filaments. J Biol Chem, 261(13): 6084–6089

[64] Grundke-IqbalI, IqbalK, TungY C, QuinlanM, WisniewskiH M, BinderL I (1986b). Abnormal phosphorylation of the microtubule-associated protein tau (τ) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA, 83(13): 4913–4917

[65] GunningP, O’NeillG, HardemanE (2008). Tropomyosin-based regulation of the actin cytoskeleton in time and space. Physiol Rev, 88(1): 1–35

[66] HaasC A, DudeckO, KirschM, HuszkaC, KannG, PollakS, ZentnerJ, FrotscherM (2002). Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci, 22(14): 5797–5802

[67] HangerD P, AndertonB H, NobleW (2009). Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med, 15(3): 112–119

[68] HayashiM L, ChoiS Y, RaoB S, JungH Y, LeeH K, ZhangD, ChattarjiS, KirkwoodA, TonegawaS (2004). Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron, 42(5): 773–787

[69] HillJ J, HashimotoT, LewisD A (2006). Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry, 11(6): 557–566

[70] HillW D, LeeV M, HurtigH I, MurrayJ M, TrojanowskiJ Q (1991). Epitopes located in spatially separate domains of each neurofilament subunit are present in Parkinson’s disease Lewy bodies. J Comp Neurol, 309(1): 150–160

[71] HouserC R (1990). Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res, 535(2): 195–204

[72] HuttonM, LendonC L, RizzuP, BakerM, FroelichS, HouldenH, Pickering-BrownS, ChakravertyS, IsaacsA, GroverA, HackettJ, AdamsonJ, LincolnS, DicksonD, DaviesP, PetersenR C, StevensM, de GraaffE, WautersE, van BarenJ, HillebrandM, JoosseM, KwonJ M, NowotnyP, CheL K, NortonJ, MorrisJ C, ReedL A, TrojanowskiJ, BasunH, LannfeltL, NeystatM, FahnS, DarkF, TannenbergT, DoddP R, HaywardN, KwokJ B, SchofieldP R, AndreadisA, SnowdenJ, CraufurdD, NearyD, OwenF, OostraB A, HardyJ, GoateA, van SwietenJ, MannD, LynchT, HeutinkP (1998). Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature, 393(6686): 702–705

[73] IngreC, LandersJE, RizikN, VolkAE, AkimotoC, BirveA, HubersA, KeaglePJ, PiotrowskaK, PressR, AndersenPM, LudolphAC, WeishauptJ H (2013). A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging, 34:1708 e1701–1706

[74] IqbalK, Grundke-IqbalI, ZaidiT, MerzP A, WenG Y, ShaikhS S, WisniewskiH M, AlafuzoffI, WinbladB (1986). Defective brain microtubule assembly in Alzheimer’s disease. Lancet, 2(8504): 421–426

[75] IttnerL M, KeY D, DelerueF, BiM, GladbachA, van EerselJ, WölfingH, ChiengB C, ChristieM J, NapierI A, EckertA, StaufenbielM, HardemanE, GötzJ (2010). Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell, 142(3): 387–397

[76] JordanovaA, De JongheP, BoerkoelC F, TakashimaH, De VriendtE, CeuterickC, MartinJ J, ButlerI J, ManciasP, PapasozomenosS Ch, TerespolskyD, PotockiL, BrownC W, ShyM, RitaD A, TournevI, KremenskyI, LupskiJ R, TimmermanV (2003). Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain, 126(Pt 3): 590–597

[77] KeY D, SuchowerskaA K, van der HovenJ, De SilvaD M, WuC W, van EerselJ, IttnerA, IttnerL M (2012). Lessons from tau-deficient mice. Int J Alzheimers Dis, 2012: 873270

[78] KimC H, LismanJ E (1999). A role of actin filament in synaptic transmission and long-term potentiation. J Neurosci, 19(11): 4314–4324

[79] KorobovaF, SvitkinaT (2008). Arp2/3 complex is important for filopodia formation, growth cone motility, and neuritogenesis in neuronal cells. Mol Biol Cell, 19(4): 1561–1574

[80] KrügerR, FischerC, SchulteT, StraussK M, MüllerT, WoitallaD, BergD, HungsM, GobbeleR, BergerK, EpplenJ T, RiessO, SchölsL (2003). Mutation analysis of the neurofilament M gene in Parkinson’s disease. Neurosci Lett, 351(2): 125–129

[81] KuhnT B, BamburgJ R (2008). Tropomyosin and ADF/cofilin as collaborators and competitors. Adv Exp Med Biol, 644: 232–249

[82] LattanteS, Le BerI, CamuzatA, BriceA, KabashiE (2013). Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France. Neurobiol Aging, 34:1709 e1701–1702

[83] LavedanC, BuchholtzS, NussbaumR L, AlbinR L, PolymeropoulosM H (2002). A mutation in the human neurofilament M gene in Parkinson’s disease that suggests a role for the cytoskeleton in neuronal degeneration. Neurosci Lett, 322(1): 57–61

[84] LeeM K, MarszalekJ R, ClevelandD W (1994). A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron, 13(4): 975–988

[85] LeeV M, GoedertM, TrojanowskiJ Q (2001). Neurodegenerative tauopathies. Annu Rev Neurosci, 24(1): 1121–1159

[86] LiB, ChohanM O, Grundke-IqbalI, IqbalK (2007). Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol, 113(5): 501–511

[87] LückingC B, DürrA, BonifatiV, VaughanJ, De MicheleG, GasserT, HarhangiB S, MecoG, DenèfleP, WoodN W, AgidY, BriceA, and the French Parkinson’s Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson’s Disease (2000). Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med, 342(21): 1560–1567

[88] LuoL, HenschT K, AckermanL, BarbelS, JanL Y, JanY N (1996). Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature, 379(6568): 837–840

[89] MaciverS K, HarringtonC R (1995). Two actin binding proteins, actin depolymerizing factor and cofilin, are associated with Hirano bodies. Neuroreport, 6(15): 1985–1988

[90] MahammadS, MurthyS N, DidonnaA, GrinB, IsraeliE, PerrotR, BomontP, JulienJ P, KuczmarskiE, OpalP, GoldmanR D (2013). Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J Clin Invest, 123(5): 1964–1975

[91] ManettoV, SternbergerN H, PerryG, SternbergerL A, GambettiP (1988). Phosphorylation of neurofilaments is altered in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol, 47(6): 642–653

[92] ManserE, LeungT, SalihuddinH, ZhaoZ S, LimL (1994). A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature, 367(6458): 40–46

[93] MatusA (1988). Microtubule-associated proteins: their potential role in determining neuronal morphology. Annu Rev Neurosci, 11(1): 29–44

[94] MinamideL S, StrieglA M, BoyleJ A, MebergP J, BamburgJ R (2000). Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nat Cell Biol, 2(9): 628–636

[95] MitchisonT J, CramerL P (1996). Actin-based cell motility and cell locomotion. Cell, 84(3): 371–379

[96] MockrinS C, KornE D (1980). Acanthamoeba profilin interacts with G-actin to increase the rate of exchange of actin-bound adenosine 5′-triphosphate. Biochemistry, 19(23): 5359–5362

[97] MorfiniG, PiginoG, MizunoN, KikkawaM, BradyS T (2007). Tau binding to microtubules does not directly affect microtubule-based vesicle motility. J Neurosci Res, 85(12): 2620–2630

[98] MoriwakiA, LuY F, TomizawaK, MatsuiH (1998). An immunosuppressant, FK506, protects against neuronal dysfunction and death but has no effect on electrographic and behavioral activities induced by systemic kainate. Neuroscience, 86(3): 855–865

[99] MorrisonB M, ShuI W, WilcoxA L, GordonJ W, MorrisonJ H (2000). Early and selective pathology of light chain neurofilament in the spinal cord and sciatic nerve of G86R mutant superoxide dismutase transgenic mice. Exp Neurol, 165(2): 207–220

[100] MunozD G, GreeneC, PerlD P, SelkoeD J (1988). Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients. J Neuropathol Exp Neurol, 47(1): 9–18

[101] Niebroj-DoboszI, DziewulskaD, JanikP (2006). Auto-antibodies against proteins of spinal cord cells in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS).Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre. Polish Academy of Sciences, 44: 191–196

[102] NishidaE, IidaK, YonezawaN, KoyasuS, YaharaI, SakaiH (1987). Cofilin is a component of intranuclear and cytoplasmic actin rods induced in cultured cells. Proc Natl Acad Sci USA, 84(15): 5262–5266

[103] NiwaR, Nagata-OhashiK, TakeichiM, MizunoK, UemuraT (2002). Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell, 108(2): 233–246

[104] OkamotoK, NagaiT, MiyawakiA, HayashiY (2004). Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci, 7(10): 1104–1112

[105] OuyangY, YangX F, HuX Y, Erbayat-AltayE, ZengL H, LeeJ M, WongM (2007). Hippocampal seizures cause depolymerization of filamentous actin in neurons independent of acute morphological changes. Brain Res, 1143: 238–246

[106] PatrickG N, ZukerbergL, NikolicM, de la MonteS, DikkesP, TsaiL H (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402(6762): 615–622

[107] PavlikL L, MoshkovD A (1991). Actin in synaptic cytoskeleton during long-term potentiation in hippocampal slices. Acta Histochem Suppl, 41(Supp 41): 257–264

[108] Pérez-OlléR, López-ToledanoM A, GoryunovD, Cabrera-PochN, StefanisL, BrownK, LiemR K (2005). Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. J Neurochem, 93(4): 861–874

[109] PerrotR, BergesR, BocquetA, EyerJ (2008). Review of the multiple aspects of neurofilament functions, and their possible contribution to neurodegeneration. Mol Neurobiol, 38(1): 27–65

[110] PowellK J, HoriS E, LeslieR, AndrieuxA, SchellinckH, ThorneM, RobertsonG S (2007). Cognitive impairments in the STOP null mouse model of schizophrenia. Behav Neurosci, 121(5): 826–835

[111] PrineasJ W, OuvrierR A, WrightR G, WalshJ C, McLeodJ G (1976). Gian axonal neuropathy—a generalized disorder of cytoplasmic microfilament formation. J Neuropathol Exp Neurol, 35(4): 458–470

[112] QiangL, YuW, AndreadisA, LuoM, BaasP W (2006). Tau protects microtubules in the axon from severing by katanin. J Neurosci, 26(12): 3120–3129

[113] RaoM V, MohanP S, KumarA, YuanA, MontagnaL, CampbellJ, Veeranna, EspreaficoE M, JulienJ P, NixonR A (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(2): e17087

[114] RenY, JiangH, YangF, NakasoK, FengJ (2009). Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J Biol Chem, 284(6): 4009–4017

[115] RenY, ZhaoJ, FengJ (2003). Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci, 23(8): 3316–3324

[116] RexC S, ChenL Y, SharmaA, LiuJ, BabayanA H, GallC M, LynchG (2009). Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol, 186(1): 85–97

[117] RossiterJ P, AndersonL L, YangF, ColeG M (2000). Caspase-cleaved actin (fractin) immunolabelling of Hirano bodies. Neuropathol Appl Neurobiol, 26(4): 342–346

[118] RossollW, JablonkaS, AndreassiC, KröningA K, KarleK, MonaniU R, SendtnerM (2003). Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol, 163(4): 801–812

[119] Rovelet-LecruxA, CampionD (2012). Copy number variations involving the microtubule-associated protein tau in human diseases. Biochem Soc Trans, 40(4): 672–676

[120] RoyS, ZhangB, LeeV M, TrojanowskiJ Q (2005). Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol, 109(1): 5–13

[121] RubioM D, HaroutunianV, Meador-WoodruffJ H (2012). Abnormalities of the Duo/Ras-related C3 botulinum toxin substrate 1/p21-activated kinase 1 pathway drive myosin light chain phosphorylation in frontal cortex in schizophrenia. Biol Psychiatry, 71(10): 906–914

[122] SánchezC, ArellanoJ I, Rodríguez-SánchezP, AvilaJ, DeFelipeJ, Díez-GuerraF J (2001). Microtubule-associated protein 2 phosphorylation is decreased in the human epileptic temporal lobe cortex. Neuroscience, 107(1): 25–33

[123] SánchezC, Díaz-NidoJ, AvilaJ (2000). Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol, 61(2): 133–168

[124] ScheibelM E, CrandallP H, ScheibelA B (1974). The hippocampal-dentate complex in temporal lobe epilepsy. A Golgi study. Epilepsia, 15(1): 55–80

[125] SchevzovG, CurthoysN M, GunningP W, FathT (2012). Functional diversity of actin cytoskeleton in neurons and its regulation by tropomyosin. Int Rev Cell Mol Biol, 298: 33–94

[126] SchmidtM L, LeeV M, TrojanowskiJ Q (1989). Analysis of epitopes shared by Hirano bodies and neurofilament proteins in normal and Alzheimer’s disease hippocampus. Lab Invest, 60(4): 513–522

[127] SchneiderA B J, BiernatJ, von BergenM, MandelkowE M, MandelkowE M (1999). Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry, 38(12): 3549–3558

[128] ScottW K, NanceM A, WattsR L, HubbleJ P, KollerW C, LyonsK, PahwaR, SternM B, ColcherA, HinerB C, JankovicJ, OndoW G, AllenF H Jr, GoetzC G, SmallG W, MastermanD, MastagliaF, LaingN G, StajichJ M, SlotterbeckB, BoozeM W, RibbleR C, RampersaudE, WestS G, GibsonR A, MiddletonL T, RosesA D, HainesJ L, ScottB L, VanceJ M, Pericak-VanceM A (2001). Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA, 286(18): 2239–2244

[129] SeitzA, KojimaH, OiwaK, MandelkowE M, SongY H, MandelkowE (2002). Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J, 21(18): 4896–4905

[130] ShimizuH, IwayamaY, YamadaK, ToyotaT, MinabeY, NakamuraK, NakajimaM, HattoriE, MoriN, OsumiN, YoshikawaT (2006). Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. Schizophr Res, 84(2–3): 244–252

[131] SousaV L, BellaniS, GiannandreaM, YousufM, ValtortaF, MeldolesiJ, ChieregattiE (2009). alpha-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell, 20(16): 3725–3739

[132] SternbergerL A, SternbergerN H (1983). Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci USA, 80(19): 6126–6130

[133] SudoH, BaasP W (2011). Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases. Hum Mol Genet, 20(4): 763–778

[134] SweetR A, HenteleffR A, ZhangW, SampsonA R, LewisD A (2009). Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology, 34(2): 374–389

[135] TakeuchiH, KobayashiY, YoshiharaT, NiwaJ, DoyuM, OhtsukaK, SobueG (2002). Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1. Brain Res, 949(1–2): 11–22

[136] TilocaC, TicozziN, PensatoV, CorradoL, Del BoR, BertolinC, FenoglioC, GagliardiS, CaliniD, LauriaG, CastellottiB, BagarottiA, CortiS, GalimbertiD, CagninA, GabelliC, RanieriM, CeroniM, SicilianoG, MazziniL, CeredaC, ScarpiniE, SoraruG, ComiGP, D'AlfonsoS, GelleraC, RattiA, LandersJE, SilaniV (2013). Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia. Neurobiol Aging, 34:1517 e1519–1510

[137] Torres-BenitoL, RuizR, TabaresL (2012). Synaptic defects in spinal muscular atrophy animal models. Dev Neurobiol, 72(1): 126–133

[138] TortelliR, RuggieriM, CorteseR, D’ErricoE, CapozzoR, LeoA, MastrapasquaM, ZoccolellaS, LeanteR, LivreaP, LogroscinoG, SimoneI L (2012). Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol, 19(12): 1561–1567

[139] TrojanowskiJ Q, LeeV M Y (2005). Rous-Whipple Award Lecture. The Alzheimer’s brain: finding out what’s broken tells us how to fix it. Am J Pathol, 167(5): 1183–1188

[140] TsengY, AnK M, EsueO, WirtzD (2004). The bimodal role of filamin in controlling the architecture and mechanics of F-actin networks. J Biol Chem, 279(3): 1819–1826

[141] van BlitterswijkM, BakerMC, BieniekKF, KnopmanDS, JosephsKA, BoeveB, CaselliR, WszolekZK, PetersenR, Graff-RadfordNR, BoylanKB, DicksonDW, RademakersR (2013). Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Amyotroph Lateral Scler Frontotemporal Degener14:463–469

[142] WagnerU, UttonM, GalloJ M, MillerC C (1996). Cellular phosphorylation of tau by GSK-3 beta influences tau binding to microtubules and microtubule organisation. J Cell Sci, 109(Pt 6): 1537–1543

[143] WongN K, HeB P, StrongM J (2000). Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS). J Neuropathol Exp Neurol, 59(11): 972–982

[144] WuC H, FalliniC, TicozziN, KeagleP J, SappP C, PiotrowskaK, LoweP, KoppersM, McKenna-YasekD, BaronD M, KostJ E, Gonzalez-PerezP, FoxA D, AdamsJ, TaroniF, TilocaC, LeclercA L, ChafeS C, MangrooD, MooreM J, ZitzewitzJ A, XuZ S, van den BergL H, GlassJ D, SicilianoG, CirulliE T, GoldsteinD B, SalachasF, MeiningerV, RossollW, RattiA, GelleraC, BoscoD A, BassellG J, SilaniV, DroryV E, BrownR H Jr, LandersJ E (2012). Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature, 488(7412): 499–503

[145] XieZ, SrivastavaD P, PhotowalaH, KaiL, CahillM E, WoolfreyK M, ShumC Y, SurmeierD J, PenzesP (2007). Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron, 56(4): 640–656

[146] XuZ, CorkL C, GriffinJ W, ClevelandD W (1993). Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell, 73(1): 23–33

[147] YangF, JiangQ, ZhaoJ, RenY, SuttonM D, FengJ (2005). Parkin stabilizes microtubules through strong binding mediated by three independent domains. J Biol Chem, 280(17): 17154–17162

[148] YangN, HiguchiO, OhashiK, NagataK, WadaA, KangawaK, NishidaE, MizunoK (1998). Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 393(6687): 809–812

[149] YangS, FifitaJ A, WilliamsK L, WarraichST, PamphlettR, NicholsonG A, BlairI P (2013). Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging, 34:2235 e2237–2210

[150] YoshiharaT, YamamotoM, HattoriN, MisuK, MoriK, KoikeH, SobueG (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(4): 221–224

[151] ZengL H, XuL, RensingN R, SinatraP M, RothmanS M, WongM (2007). Kainate seizures cause acute dendritic injury and actin depolymerization in vivo. J Neurosci, 27(43): 11604–11613

[152] ZhangB, CarrollJ, TrojanowskiJ Q, YaoY, IbaM, PotuzakJ S, HoganA M L, XieS X, BallatoreC, SmithA B 3rd, LeeV M L, BrundenK R (2012). The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci, 32(11): 3601–3611

[153] ZhangB, MaitiA, ShivelyS, LakhaniF, McDonald-JonesG, BruceJ, LeeE B, XieS X, JoyceS, LiC, ToleikisP M, LeeV M, TrojanowskiJ Q (2005). Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci USA, 102(1): 227–231

[154] ZhangW, BensonD L (2001). Stages of synapse development defined by dependence on F-actin. J Neurosci,21:5169–5181

[155] ZhuQ, Couillard-DesprésS, JulienJ P (1997). Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol, 148(1): 299–316

[156] ZouZY, SunQ, LiuMS, LiXG, CuiLY (2013). Mutations in the profilin 1 gene are not common in amyotrophic lateral sclerosis of Chinese origin. Neurobiol Aging, 34:1713 e1715–1716

Acknowledgements

We thank Dr. Anthony Kee for critical reading of the manuscript and for the support from Australian Research Council Discovery Project Grant 110102771.

Compliance with ethic guidelines

Alexandra K. Suchowerska and Thomas Fath declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg