Synaptic dysfunction and septin protein family members in neurodegenerative diseases

Molecular Neurodegeneration

Mikko Hiltunen¹  Annakaisa Haapasalo¹  Hilkka Soininen¹  Kaisa MA Kurkinen¹  Mikael Marttinen¹ 

[1]Department of Neurology, Kuopio University Hospital, Kuopio, Finland

关键词: Synaptic plasticity;    Synaptic dysfunction;    Septin;    Parkinson’s disease;    Neurodegeneration;    Long-term potentiation;    Huntington’s disease long-term depression;    Frontotemporal lobar degeneration;    Alzheimer’s disease;   

Others  :  1170913
DOI  :  10.1186/s13024-015-0013-z

 received in 2014-12-15, accepted in 2015-03-23,  发布年份 2015

【 摘 要 】

Cognitive decline and disease progression in different neurodegenerative diseases typically involves synaptic dysfunction preceding the neuronal loss. The synaptic dysfunction is suggested to be caused by imbalanced synaptic plasticity i.e. enhanced induction of long-term depression and concomitantly decreased long-term potentiation accompanied with excess stimulation of extrasynaptic N-Methyl-D-aspartate (NMDA) receptors due to various disturbances in pre- and postsynaptic sites. Recent research has identified neurodegenerative disease-related changes in protein accumulation and aggregation, gene expression, and protein functions, which may contribute to imbalanced synaptic function. Nevertheless, a comprehensive understanding of the mechanisms regulating synaptic plasticity in health and disease is still lacking and therefore characterization of new candidates involved in these mechanisms is needed. Septins, a highly conserved group of guanosine-5'-triphosphate (GTP)-binding proteins, show high neuronal expression and are implicated in the regulation of synaptic vesicle trafficking and neurotransmitter release. In this review, we first summarize the evidence how synaptic dysfunction is related to the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s disease and frontotemporal lobar degeneration. Then, we discuss different aspects of the potential involvement of the septin family members in the regulation of synaptic function in relation to the pathogenesis of neurodegenerative diseases.

【 授权许可】

   
2015 Marttinen et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Cooke SF, Bliss TV: Plasticity in the human central nervous system. Brain 2006, 129:1659-73.
• [2]Eidelberg D, Surmeier DJ: Brain networks in Huntington disease. J Clin Invest 2011, 121:484-92.
• [3]Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, et al.: Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 2005, 45:489-96.
• [4]Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D: Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009, 62:788-801.
• [5]Oh MC, Derkach VA, Guire ES, Soderling TR: Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 2006, 281:752-8.
• [6]Malenka RC, Bear MF: LTP and LTD: an embarrassment of riches. Neuron 2004, 44:5-21.
• [7]Hardingham GE, Bading H: Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010, 11:682-96.
• [8]Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27:2866-75.
• [9]Minano-Molina AJ, Espana J, Martin E, Barneda-Zahonero B, Fado R, Sole M, et al.: Soluble oligomers of amyloid-beta peptide disrupt membrane trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction. J Biol Chem 2011, 286:27311-21.
• [10]Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, et al.: Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 2010, 65:66-79.
• [11]Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al.: Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 2013, 110:E2518-27.
• [12]Hall PA, Russell SE: The pathobiology of the septin gene family. J Pathol 2004, 204:489-505.
• [13]Cummings JL: Alzheimer's disease. N Engl J Med 2004, 351:56-67.
• [14]DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 1990, 27:457-64.
• [15]Mandelkow EM, Mandelkow E: Tau in Alzheimer's disease. Trends Cell Biol 1998, 8:425-7.
• [16]Neve RL, McPhie DL, Chen Y: Alzheimer's disease: a dysfunction of the amyloid precursor protein(1). Brain Res 2000, 886:54-66.
• [17]De Strooper B: Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 2010, 90:465-94.
• [18]Vetrivel KS, Thinakaran G: Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 2006, 66:S69-73.
• [19]Zhang H, Ma Q, Zhang YW, Xu H: Proteolytic processing of Alzheimer's beta-amyloid precursor protein. J Neurochem 2012, 120(Suppl 1):9-21.
• [20]Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer's disease. Mol Brain. 2011;4:3-6606-4-3.
• [21]Hu X, Li X, Zhao M, Gottesdiener A, Luo W, Paul S: Tau pathogenesis is promoted by Abeta1-42 but not Abeta1-40. Mol Neurodegener 2014, 9:52.
• [22]Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, et al.: Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J 2010, 29:3408-20.
• [23]De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, et al.: Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 2007, 282:11590-601.
• [24]Coleman PD, Yao PJ: Synaptic slaughter in Alzheimer's disease. Neurobiol Aging 2003, 24:1023-7.
• [25]Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al.: A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012, 488:96-9.
• [26]Hashimoto Y, Matsuoka M: A mutation protective against Alzheimer's disease renders amyloid beta precursor protein incapable of mediating neurotoxicity. J Neurochem 2014, 130:291-300.
• [27]Karran E, Mercken M, De Strooper B: The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011, 10:698-712.
• [28]Kopeikina KJ, Hyman BT, Spires-Jones TL: Soluble forms of tau are toxic in Alzheimer's disease. Transl Neurosci 2012, 3:223-33.
• [29]Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al.: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416:535-9.
• [30]Selkoe DJ: Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 2008, 192:106-13.
• [31]Frandemiche ML, De Seranno S, Rush T, Borel E, Elie A, Arnal I, et al.: Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci 2014, 34:6084-97.
• [32]Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al.: Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010, 142:387-97.
• [33]Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al.: Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007, 316:750-4.
• [34]Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE: Evidence for impaired amyloid beta clearance in Alzheimer's disease. Alzheimers Res Ther 2013, 5:33.
• [35]Chen X, Lin R, Chang L, Xu S, Wei X, Zhang J, et al.: Enhancement of long-term depression by soluble amyloid beta protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3. Neuroscience 2013, 253:435-43.
• [36]Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, et al.: Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci 2011, 14:545-7.
• [37]Liu CC, Tsai CW, Deak F, Rogers J, Penuliar M, Sung YM, et al.: Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease. Neuron 2014, 84:63-77.
• [38]Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, et al.: LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 2007, 53:703-17.
• [39]de la Monte SM: Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Curr Alzheimer Res 2012, 9:35-66.
• [40]Han X, Ma Y, Liu X, Wang L, Qi S, Zhang Q, et al.: Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer's disease rat model. J Neural Transm 2012, 119:1407-16.
• [41]Zhao WQ, Chen H, Quon MJ, Alkon DL: Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004, 490:71-81.
• [42]Cerpa W, Godoy JA, Alfaro I, Farias GG, Metcalfe MJ, Fuentealba R, et al.: Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem 2008, 283:5918-27.
• [43]Cerpa W, Gambrill A, Inestrosa NC, Barria A: Regulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci 2011, 31:9466-71.
• [44]Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, et al.: Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimers Dis 2007, 11:97-116.
• [45]Wang Y, Briz V, Chishti A, Bi X, Baudry M: Distinct roles for mu-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration. J Neurosci 2013, 33:18880-92.
• [46]Dominguez E, Chin TY, Chen CP, Wu TY: Management of moderate to severe Alzheimer's disease: focus on memantine. Taiwan J Obstet Gynecol 2011, 50:415-23.
• [47]Tucci P, Mhillaj E, Morgese MG, Colaianna M, Zotti M, Schiavone S, et al.: Memantine prevents memory consolidation failure induced by soluble beta amyloid in rats. Front Behav Neurosci 2014, 8:332.
• [48]Xia P, Chen HS, Zhang D, Lipton SA: Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci 2010, 30:11246-50.
• [49]Sinforiani E, Pasotti C, Chiapella L, Malinverni P, Zucchella C: Memantine in Alzheimer's disease: experience in an Alzheimer's disease assessment unit. Aging Clin Exp Res 2012, 24:193-6.
• [50]Emre M, Tsolaki M, Bonuccelli U, Destee A, Tolosa E, Kutzelnigg A, et al.: Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010, 9:969-77.
• [51]Wesnes KA, Aarsland D, Ballard C, Londos E: Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry 2014, 30:46-54.
• [52]Ballatore C, Lee VM, Trojanowski JQ: Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 2007, 8:663-72.
• [53]Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ: Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 2011, 31:6627-38.
• [54]Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, et al.: Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010, 68:1067-81.
• [55]Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, et al.: Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem 2001, 276:693-9.
• [56]Rong Y, Lu X, Bernard A, Khrestchatisky M, Baudry M: Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. J Neurochem 2001, 79:382-90.
• [57]Salter MW, Kalia LV: Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 2004, 5:317-28.
• [58]Graff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, et al.: An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012, 483:222-6.
• [59]Bie B, Wu J, Yang H, Xu JJ, Brown DL, Naguib M: Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nat Neurosci 2014, 17:223-31.
• [60]Luo P, Li X, Fei Z, Poon W: Scaffold protein Homer 1: implications for neurological diseases. Neurochem Int 2012, 61:731-8.
• [61]Mishiba T, Tanaka M, Mita N, He X, Sasamoto K, Itohara S, et al.: Cdk5/p35 functions as a crucial regulator of spatial learning and memory. Mol Brain 2014, 7:82.
• [62]Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ, Feske S, et al.: Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 2014, 82:79-93.
• [63]Liu J, Chang L, Roselli F, Almeida OF, Gao X, Wang X, et al.: Amyloid-beta induces caspase-dependent loss of PSD-95 and synaptophysin through NMDA receptors. J Alzheimers Dis 2010, 22:541-56.
• [64]Ni R, Marutle A, Nordberg A: Modulation of alpha7 nicotinic acetylcholine receptor and fibrillar amyloid-beta interactions in Alzheimer's disease brain. J Alzheimers Dis 2013, 33:841-51.
• [65]Rushworth JV, Griffiths HH, Watt NT, Hooper NM: Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1. J Biol Chem 2013, 288:8935-51.
• [66]Calabresi P, Maj R, Pisani A, Mercuri NB, Bernardi G: Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J Neurosci 1992, 12:4224-33.
• [67]Ferrer I: Neurons and their dendrites in frontotemporal dementia. Dement Geriatr Cogn Disord 1999, 10(Suppl 1):55-60.
• [68]Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G, et al.: Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci 2003, 6:501-6.
• [69]Raymond LA, Andre VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS: Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience 2011, 198:252-73.
• [70]Lesage S, Brice A: Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009, 18:R48-59.
• [71]Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al.: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998, 392:605-8.
• [72]Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al.: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004, 55:164-73.
• [73]Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al.: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004, 44:601-7.
• [74]Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC: Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329:1663-7.
• [75]Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997, 388:839-40.
• [76]Dalfo E, Gomez-Isla T, Rosa JL, Nieto Bodelon M, Cuadrado Tejedor M, Barrachina M, et al.: Abnormal alpha-synuclein interactions with Rab proteins in alpha-synuclein A30P transgenic mice. J Neuropathol Exp Neurol 2004, 63:302-13.
• [77]Dalfo E, Barrachina M, Rosa JL, Ambrosio S, Ferrer I: Abnormal alpha-synuclein interactions with rab3a and rabphilin in diffuse Lewy body disease. Neurobiol Dis 2004, 16:92-7.
• [78]Piccoli G, Condliffe SB, Bauer M, Giesert F, Boldt K, De Astis S, et al.: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci 2011, 31:2225-37.
• [79]Shin N, Jeong H, Kwon J, Heo HY, Kwon JJ, Yun HJ, et al.: LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 2008, 314:2055-65.
• [80]Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, et al.: GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 2010, 6:e1000902.
• [81]Anonymous: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group Cell 1993, 72:971-83.
• [82]Ross CA, Tabrizi SJ: Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011, 10:83-98.
• [83]Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, et al.: In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum Mol Genet 2010, 19:3053-67.
• [84]Estrada-Sanchez AM, Rebec GV: Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: interactions between neurons and astrocytes. Basal Ganglia 2012, 2:57-66.
• [85]Miller BR, Dorner JL, Bunner KD, Gaither TW, Klein EL, Barton SJ, et al.: Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease. J Neurochem 2012, 121:629-38.
• [86]Corti C, Battaglia G, Molinaro G, Riozzi B, Pittaluga A, Corsi M, et al.: The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection. J Neurosci 2007, 27:8297-308.
• [87]Ondo WG, Mejia NI, Hunter CB: A pilot study of the clinical efficacy and safety of memantine for Huntington's disease. Parkinsonism Relat Disord 2007, 13:453-4.
• [88]Brun A, Liu X, Erikson C: Synapse loss and gliosis in the molecular layer of the cerebral cortex in Alzheimer's disease and in frontal lobe degeneration. Neurodegeneration 1995, 4:171-7.
• [89]Liu X, Erikson C, Brun A: Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration. Dementia 1996, 7:128-34.
• [90]Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al.: Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009, 117:15-8.
• [91]DeMay BS, Bai X, Howard L, Occhipinti P, Meseroll RA, Spiliotis ET, et al.: Septin filaments exhibit a dynamic, paired organization that is conserved from yeast to mammals. J Cell Biol 2011, 193:1065-81.
• [92]Yang YM, Fedchyshyn MJ, Grande G, Aitoubah J, Tsang CW, Xie H, et al.: Septins regulate developmental switching from microdomain to nanodomain coupling of Ca(2+) influx to neurotransmitter release at a central synapse. Neuron 2010, 67:100-15.
• [93]Amin ND, Zheng YL, Kesavapany S, Kanungo J, Guszczynski T, Sihag RK, et al.: Cyclin-dependent kinase 5 phosphorylation of human septin SEPT5 (hCDCrel-1) modulates exocytosis. J Neurosci 2008, 28:3631-43.
• [94]Ito H, Atsuzawa K, Morishita R, Usuda N, Sudo K, Iwamoto I, et al.: Sept8 controls the binding of vesicle-associated membrane protein 2 to synaptophysin. J Neurochem 2009, 108:867-80.
• [95]Hall PA, Russell SE: Mammalian septins: dynamic heteromers with roles in cellular morphogenesis and compartmentalization. J Pathol 2012, 226:287-99.
• [96]Mavrakis M, Azou-Gros Y, Tsai FC, Alvarado J, Bertin A, Iv F, et al.: Septins promote F-actin ring formation by crosslinking actin filaments into curved bundles. Nat Cell Biol 2014, 16:322-34.
• [97]Munoz-Soriano V, Paricio N: Overexpression of Septin 4, the Drosophila homologue of human CDCrel-1, is toxic for dopaminergic neurons. Eur J Neurosci 2007, 26:3150-8.
• [98]Kinoshita A, Kinoshita M, Akiyama H, Tomimoto H, Akiguchi I, Kumar S, et al.: Identification of septins in neurofibrillary tangles in Alzheimer's disease. Am J Pathol 1998, 153:1551-60.
• [99]Barr AM, Young CE, Sawada K, Trimble WS, Phillips AG, Honer WG: Abnormalities of presynaptic protein CDCrel-1 in striatum of rats reared in social isolation: relevance to neural connectivity in schizophrenia. Eur J Neurosci 2004, 20:303-7.
• [100]Mostowy S, Cossart P: Septins: the fourth component of the cytoskeleton. Nat Rev Mol Cell Biol 2012, 13:183-94.
• [101]Beise N, Trimble W: Septins at a glance. J Cell Sci 2011, 124:4141-6.
• [102]Peterson EA, Petty EM: Conquering the complex world of human septins: implications for health and disease. Clin Genet 2010, 77:511-24.
• [103]Oh Y, Bi E: Septin structure and function in yeast and beyond. Trends Cell Biol 2011, 21:141-8.
• [104]Weirich CS, Erzberger JP, Barral Y: The septin family of GTPases: architecture and dynamics. Nat Rev Mol Cell Biol 2008, 9:478-89.
• [105]Sirajuddin M, Farkasovsky M, Zent E, Wittinghofer A: GTP-induced conformational changes in septins and implications for function. Proc Natl Acad Sci U S A 2009, 106:16592-7.
• [106]Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M. Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. Mol Brain. 2013;6:35-6606-6-35.
• [107]Dong Z, Ferger B, Paterna JC, Vogel D, Furler S, Osinde M, et al.: Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A 2003, 100:12438-43.
• [108]Gozal YM, Seyfried NT, Gearing M, Glass JD, Heilman CJ, Wuu J, et al. Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration. Mol Neurodegener. 2011;6:82-1326-6-82.
• [109]Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, et al.: Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 2007, 53:519-33.
• [110]Pissuti Damalio JC, Garcia W, Alves Macedo JN, de Almeida Marques I, Andreu JM, Giraldo R, et al.: Self assembly of human septin 2 into amyloid filaments. Biochimie 2012, 94:628-36.
• [111]Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM: Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A 2000, 97:13354-9.
• [112]Musunuri S, Wetterhall M, Ingelsson M, Lannfelt L, Artemenko K, Bergquist J, et al.: Quantification of the Brain Proteome in Alzheimer's Disease Using Multiplexed Mass Spectrometry. J. Proteome Res 2014, 13:2056-68.
• [113]Takehashi M, Alioto T, Stedeford T, Persad A, Banasik M, Masliah E, et al. Septin 3 gene polymorphism in Alzheimer's disease. 2004;11:263-70.
• [114]Hanai N, Nagata K, Kawajiri A, Shiromizu T, Saitoh N, Hasegawa Y, et al.: Biochemical and cell biological characterization of a mammalian septin, Sept11. FEBS Lett 2004, 568:83-8.
• [115]Cairns NJ, Lee VM, Trojanowski JQ: The cytoskeleton in neurodegenerative diseases. J Pathol 2004, 204:438-49.
• [116]Czeredys M, Gruszczynska-Biegala J, Schacht T, Methner A, Kuznicki J: Expression of genes encoding the calcium signalosome in cellular and transgenic models of Huntington's disease. Front Mol Neurosci 2013, 6:42.
• [117]Taniguchi M, Taoka M, Itakura M, Asada A, Saito T, Kinoshita M, et al.: Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1. J Biol Chem 2007, 282:7869-76.
• [118]Beites CL, Xie H, Bowser R, Trimble WS: The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nat Neurosci 1999, 2:434-9.
• [119]Shukla V, Skuntz S, Pant HC: Deregulated Cdk5 activity is involved in inducing Alzheimer's disease. Arch Med Res 2012, 43:655-62.
• [120]Son JH, Kawamata H, Yoo MS, Kim DJ, Lee YK, Kim S, et al.: Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons. J Neurochem 2005, 94:1040-53.
• [121]Kinoshita N, Kimura K, Matsumoto N, Watanabe M, Fukaya M, Ide C: Mammalian septin Sept2 modulates the activity of GLAST, a glutamate transporter in astrocytes. Genes Cells 2004, 9:1-14.
• [122]Sitz JH, Baumgartel K, Hammerle B, Papadopoulos C, Hekerman P, Tejedor FJ, et al.: The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4. Neuroscience 2008, 157:596-605.
• [123]Ihara M, Tomimoto H, Kitayama H, Morioka Y, Akiguchi I, Shibasaki H, et al.: Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies. J Biol Chem 2003, 278:24095-102.
• [124]Kissel H, Georgescu MM, Larisch S, Manova K, Hunnicutt GR, Steller H: The Sept4 septin locus is required for sperm terminal differentiation in mice. Dev Cell 2005, 8:353-64.
• [125]Garcia-Fernandez M, Kissel H, Brown S, Gorenc T, Schile AJ, Rafii S, et al.: Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes Dev 2010, 24:2282-93.
• [126]Tokhtaeva E, Capri J, Marcus EA, Whitelegge JP, Khuzakhmetova V, Bukharaeva E, et al.: Septin dynamics are essential for exocytosis. J Biol Chem 2015, 290:5280-97.
• [127]Kvartsberg H, Duits FH, Ingelsson M, Andreasen N, Ohrfelt A, Andersson K, et al. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement 2014, doi:10.1016/j.jalz.2014.10.009.
• [128]Brinkmalm A, Brinkmalm G, Honer WG, Frolich L, Hausner L, Minthon L, et al.: SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol Neurodegener 2014, 9:53-1326. 9-53
• [129]Katsuno M, Tanaka F, Sobue G: Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases. J Neurol Neurosurg Psychiatry 2012, 83:329-35.