Journal of Cell Science nttt,Oagbr,NwYr,N 06,USA 10962, NY York, New Orangeburg, Institute, iogYuan Aidong glance a at Neurofilaments Glance a at Science Cell r rsn nprkraaddendrites, and nm, perikarya 10 they in of Although present neurons. diameter of are that a to intermediate similar with are filaments (NFs) Neurofilaments 10.1242/jcs.104729 doi: 3257–3263 125, ß Science Cell of Journal [email protected] ( correspondence for *Authors 2 1 e ok Y106 USA 10016, Medicine, NY of York, School New University York New Biology, Nixon Veeranna eateto scityand Psychiatry of Department Kline Nathan Research, Dementia for Center 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. 1,2,3, 1,2 * ) n ap A. Ralph and 1,2, ,Ml .Rao V. Mala *, [email protected] 3 eateto Cell of Department ; 1,2 , xn,weete r seta o h radial the for essential in are they where abundant axons, particularly are neurofilaments erpty(A) ibtcneuropathy, axonal diabetic giant (GAN), (NFID), neuropathy other disease Charcot- of inclusion as neurofilament disease, sufferers (CMT) such Marie-Tooth diseases, in neurological prominent are they also but lesion, a pathological are hallmark al., accumulations these et lateral (ALS), Munoz amyotrophic sclerosis affected with 2009; patients In al., of 1988). et axons (Liu cell proximal neurons within and some numbers bodies In large 1997). in al., accumulate et can neurofilaments Zhu conditions, and pathological 2009; Friede al., Yum 1993; et al., 1994; et conduction Ohara Peterson, 1970; Samorajski, nerve the and of and (Eyer velocity along i.e. caliber impulses axons, electrical axon of transmission of the development, during maintenance axons of growth erflmn ev,mdu n light namely and subunits, medium four that heavy, of neurofilament heteropolymers composed are are nervous (CNS) central system the from Neurofilaments function and structure Neurofilament disease. current and health the review in functions neurofilament we of understanding article, Glance a at Science Cell this In 1998). al., et Williamson ta. 93 Couillard-Despre 1993; al., et (Co process pathogenic being the simply of by-products than NF the rather of aberrant neurons, death affected these the to that contribute accumulations idea models and the mouse Szaro support Transgenic 2009; 2010). Eyer, al., Strong, and et Perrot (Abe 2009; (PD) disease (AD) Parkinson’s disease and Alzheimer’s from people those suffer in that present are and spastic paraplegia, and (SMA) atrophy muscular spinal Sepse insert) poster (See ´ setal.,1998; 3257 ˆ te ´ Journal of Cell Science ta. 01 a ta. 01.N subunits NF Kim 2011). al., 2008; et Rao al., 2011; al., axoplasmic docking et et the different (Balastik for of constituents scaffold organization a and of general the properties assembly) NF heteropolymer panel, the poster (see to confer NF which each subunit, in domains protein the for identified the (Kriz of 2000). axons of determinants dimensions being physical beyond roles in Nefh observed is velocity conduction but decreased caliber axonal normal However, 2000). ieta lack knockout that in and mice 2007), al., et (Perrot axons into transport gene NF with interferes that NFL protein NFH– a mice the transgenic expressing in 1993), in al., mutant et a (Sakaguchi of mutation in because NFs nonsense observed lack that conduction been quail Japanese reduced has by velocity axon accompanied that caliber for is axon crucial Decreased growth. is radial phosphorylation not but tail domain tail and NFM the 2009), calibers that al., tail indicating et axon (Garcia the velocities normal conduction along have sites domain (Lys-Ser-Pro) expressing at phosphorylation mice KSP lack 2003), that subunits al., NFM al., et et Rao (Garcia 2003; velocities conduction reduces NFM and their axons of of growth domain radial inhibits tail phosphorylated al., the of deletion Although et 1997). al., Ohara et Zhu 1998; 1993; especially al., are et subunits (Elder important NFM and and 1987) NFL al., the et and Hoffman (Eyer 1994; growth are Peterson, radial Neurofilaments axon for 2007). required al., neurons et of (Wagner shape the asymmetrical maintain markedly to fibrous them elastic enable their their that and properties 2009) 1986; al., Logvinenko, are et and Yuan Nixon 2007; NFs al., (Millecamps et half-lives of long the exceptionally Among properties 1998). NFL al., human et notable – (Carter self- vitro so in do filaments, to can least at homopolymer unable – although are into NFM subunits NFH, assemble other Mouse NFL 2005). vimentin and al., express and et syncoilin (Perrin 2006b). including synemin, also al., proteins, nestin, et filament may Yuan intermediate 2007; al., Neurons 1999; et al., et Yan (Beaulieu peripherin NFM, and NFH, NFL of system, up made nervous are peripheral neurofilaments the as NFL, in well whereas as and NEFL), NEFM NEFH, and as NFM known also respectively; (NFH, polypeptides 3258 ubro pcfcrlshv been have roles specific of number A nl ie niaigta F have NFs that indicating mice, -null ora fCl cec 2 (14) 125 Science Cell of Journal Nefl b or glcoiaefusion -galactosidase Nefm a itrei (Int), -internexin (Kriz ˇ ˇ tal., et tal., et oan n aibeti oan htdiffer that domains an tail variable head, and domain, globular a contain uas uain nNLaeassociated these are In NFL clear. of in although yet mutations not 2002), humans, significance is al., interactions intriguing functional et (Kim the NFM C-terminus the of with receptor associates D1 dopamine selectively the (Ehlers and 1998), NFL al., with et associates receptor NR1 subunit (NMDA) N-methyl-D-aspartate 2010). al., (Kushkuley et the Kushkuley cations and 2009; al., 1998) divalent by et al., by et (Eyer influenced Gou mediated tails 1988; be these Leterrier, and of 2002). to level NFM al., phosphorylation believed and NFH et neurofilaments of is domains Rao tail the between 2003; through al., NFH Crossbridging of et that than C- axons (Rao of The growth important radial more for expansion. is NFM of caliber domain terminal space axon occupy that to during thereby ability extensions NFs, their between lateral maximizing spacing the fine and increase NFH form these 2011). both al., of NFM depletes et domains C-terminal (Rao partially The axons NFL Va from of organelles Loss myosin 2011). (ER, the al., or et within organelles (Rao vesicles) axoplasm topography vesicular synaptic local endosomes, which specific and protein, of motor levels Va modulates myosin site the binding a for as serve NF and NFs, of into polymerization subunits axon the in the have roles domains in important rod that The MTs 2009). al., of et (Bocquet domain number the regulates inhibitory head (MT) The microtubule a polymerization have filaments. NFs all form of domains to other with subunits co-assembly NF that the domain for highly rod important is acid a amino 310 contains conserved subunit Each composition. acid neurofilament amino and length in ml ubro prdcASpatients ALS sporadic a of in identified number been have small gene NFH Mutations the 2002). in al., et (Lavedan early- PD in onset domain identified rod been occasionally NFM have the al., upon of et and, (Yates Mutations transport 2009). 2006) NF inhibit al., can that, et (Sasaki the in NFs neurons of assembly the These affect mutations disease. Charcot-Marie-Tooth with nel xnltasoto neurofilament of transport are axonal that underly mechanisms reach The function. to of axons sites proteins their along must distances and long body travel cell the neurofilament within synthesized Most transport Neurofilament 2003). Miller, and (Al-Chalabi neetnl,aslc ain fthe of variant splice a Interestingly, a hlclrod -helical F obekoku iei esthan less is NFH- mice of of knockout axons we double number optic NFL instance, the in For that neurofilaments 2006b). demonstrated al., have et NF Yuan 2003; of al., of formation et (Yuan the neurofilaments complete require transport not does that subunits however, have mice genes shown, subunit in NF more al., Studies or one 2000). lack et that al., et (Trivedi Wang axons 2007; growing NF-poor filaments short (1.0–15.8 individual visualize directly of to movements able were and colleagues by Brown culture, protein in example, neurons sympathetic developing fluorescent into For subunits NF 2009). (GFP)-labeled green al., transfecting et 2006b; al., et al., Yuan Yuan et 2003; Yabe al., 2000; et Yuan al., 1999; et Wang 2000; al., the (Roy et neurofilaments regarding have of behaviors principles dynamic approaches general imaging yielded live-cell and genetic recent although elusive, are proteins te ye fclue el n ntesquid the in and cells cultured short in of types observed however, other been 1999); also al., have neurofilaments et Yabe al., et 2000; (Prahlad reported been have non- subunits NF GFP-labeled represent of that assemblies Movementfilamentous puncta 1997). fluorescent or Brown, al., of support et and subunit Hirokawa (Baas or 1997; to assemblies polymers oligomer amassed of indirect movement being past considerably the with evidence during decades, debate three of and area active investigation of an became state transport during axonal The proteins neurofilament 1984). of assembly Liem, and role (Pachter transport crucial and partnership neurofilament its for indicating further appear, neurofilaments definable morphologically before axons these in detectable NFL are and subunits NFM why explains axons optic rat The 2006b). al., of et presence early Yuan 2003; al., 2006a; et al., Yuan et (Yuan axons optic in transport or NFM alters both, minimally or only NFL NFH, either deleting whereas NFH, deleting and/or as NFL of NFs, transport prevents or both dimers of for transport crucial the are of NF that subunits the as formation specific identified and involve the NFM subunits. that is for heterodimers requirement transport minimal axonal the that have deletions shown subunit NF of combinations 2003). al., et (Yuan rates axons transport typical along at level move usual which the subunits, NFM of of 50% have mice these neurofilaments, yet of number usual the of 10% ute tde ihdifferent with studies Further m nlnt)aogterelatively the along length) in m a itrei ndeveloping in -internexin a itrei aebeen have -internexin a -internexin Journal of Cell Science ta. 01,a ela oeetof movement as well (Yabe as 2001), cells been al., neuroblastoma also et has in NF filaments non-filamentous reported and 2005). both Brown, oligomers and of Yan 2000; Transport al., et Roy 1999; al., et Galbraith 2003; used al., methods et (Ackerley the on depending axon, giant N sRA a ensonto NF shown retrograde been decrease has significantly (siRNA) the RNA of interference al., small using expression chain et heavy dynein of (Wagner Knockdown assays 2004). hybrid in interacts subunit two NFM dynein the yeast of and domain NF rod 2000) the with with al., et co-purifies (Shah for complex motor dynein– the dynactin retrograde because NF the of transport axonal be to is NF believed complex for dynein-dynactin motor cultured anterograde The an transport. as in acts suggest kinesin-I it 2010) transport that Brown, of and NF (Wang effect neurons on the of mutation of analyses 2003) al., isoform and et (Xia (an mice knockout kinesin-IA kinesin-I) from it partners. Studies subunit motor, NF transport additional have NF al., would the et were NF if Yuan that, kinesin-I implying 2006b), 2002; for al., et al., dispensable Yuan 2006a; et is (Rao have NFH transport studies that later However, found 1999). antibody al., because et (Yabe transport and NF blocks 2005; 2000) kinesin-I against al., al., et et (Jung the Yabe subunits with anterograde NFM interacts or an it NFH because be NF to for motor proposed Kinesin-I 2009). been motor al., has et (Alami microfilament-based al., Va et fast myosin Sunil and 2000; the and al., 2012), be et kinesin (Prahlad to dynein motors believed microtubule-based are transport 2009). al., et (Yuan transport during axonal transported filaments into the assemble axonal subunits that NF suggest during in and forms exist transport might assembly proteins the multiple NF of that levels establish observations these distal Collectively, axon. at same predominates NFs short of transport the whereas thesepredominates, assemblies subunit in of transport levels the al., axonal neurons, et proximal (Yuan At axon 2009). be subunit same can the polymers in NF transported NF short non-filamentous and assemblies both that demonstrating by cortical observations apparently cultured conflicting, these, reconcile in further GFP- protein neurons Our NFL of 1998). hamster tagged analyses al., photobleaching baby et recent (Prahlad spreading cells and kidney in particles filaments non-filamentous vimentin h oeua oosta euaeNF regulate that motors molecular The rnpr.O h ai fti current this of basis the axonal through On loss by transport. explained be could diinlseso nerto noa remain still into that which events integration regulatory network, involves neurofilament of stationary steps undergo subsequently the additional they of or filament), oligomer short dimer, Regardless (i.e. proteins transport neurofilament during 2001). take that form al., assembly et 1992; Shea, Yabe and and (Nixon type state cell developmental on depending assembly vary different might forms these of subunits. be NF proportions either of The is oligomers can or elements polymers These short that and 2009). al., stationary (Yuan et structure elements transported large from assembled stable a is as metabolically network viewed neurofilament Yuan the 2007; now 2009), al., al., et et (Millecamps evidence 09.Dsieteeavne,the advances, these al., et Despite Uchida 2005; al., 2009). et (He transport hssuydmntae htpre- that slow ( exceptionally turnover remain an display axon demonstrates and the stationary in neurofilaments study 2007). existing pre-existing al., the et This of (Millecamps fate neurofilaments the measuring by followed mouse, knockout NFL in conditional in off a shut colleagues, acutely was and expression Julien NFL which by study turnover vivo NF in an of including 2007; 2009), al., al., et et Yuan (Millecamps model to general support this added studies Later the of cytoskeleton. cytoskeletal images ultrastructural in various visible are filaments) that the actin microtubules, (NF, of elements composed a within is that exists network cytoskeletal turn, stationary in complex NF lattice, fixed This pre-existing lattice. large pool a precursor maintains small in that a transport are axons and slow myelinated oligomeric undergo (or that (Nixon neurofilaments assemblies) that system idea supported the studies optic These 1986). Logvinenko, mouse using the by pulse-labeling model, on months) exceptionally (6 and authors short long-term different of the studies of A by basis the proposed 1992). 1984; was al., however, al., is et et labeled model, Lasek (Lasek this moving to the transport continuously according within which, that cytoskeleton undergo axons, NF entire the idea that constitute the neurofilaments to interpreted initially support were Lasek colleagues by and transport protein neurofilament live of in or neurons cultured animals. in live-cell has by imaging visualized motors directly been and yet not NFs between interaction h aleti ioplelbln studies pulse-labeling vivo in earliest The . . ots uhlne than longer much – months) 2.5 ora fCl cec 2 1)3259 (14) 125 Science Cell of Journal osbyas yCmkns I(Hashimoto II and kinase Cam 1990) by Nixon, also and and possibly Sihag Sihag 1988; al., 1989; et Nixon, (Sihag (PKA) (PKC) A C kinase and protein kinases dependent messenger second the head by Vosseller mediated NF is 1993; domain the of al., Phosphorylation 2006). et al., Tanaka et 2008; Manser al., 1996; et al., et NFM, (Dong glycosylated NFL, and of and domains al., NFH head as et The (Perrot 2008). ubiquitylation nitration, such and oxidation post- glycosylation, modifications, phosphorylation, various translational undergo Neurofilaments phosphorylation Neurofilament Yuan 2003; 2009). al., al., et et (Yuan explored fully be to sha hshrlto fNLihbt NF inhibits NFL of phosphorylation head NFs, as of state role disassembled the suggested maintaining its in after head reflects soon NF synthesis body of subunit cell occurrence the in The phosphorylation 2000). al., et yatgnss(adne l,1987; al., and et myelination on (Carden depend synaptogenesis panel to appears poster phosphorylation regulated head developmentally (see This NF phosphorylation). Tail phosphorylated neurofilaments: phosphorylation, axons of highly Modification mature become in bodies, cell non-phosphorylated the which in with found predominately cell, tails regions the particular for within the specific of is Phosphorylation domain tail 1987). 1989; 1983; al., al., et et Mushynski, extensively Nixon Nixon 1986; and Lewis, are and (Julien Nixon NFM NFH they of domains and tail axon the move on and phosphorylated the enter NFs protein the along al., after multiple et Soon (Veeranna 2011). by phosphatases and regulated of kinases status is phosphorylation which the lysine-serine-proline sites, multiple (KSP) have NFH Saito 1986; 1995). phosphatase Lewis, al., and et protein domain, (Nixon by (PP2A) head 2A effected is the requires which axon of the phosphates along dephosphorylation of transit turnover their the rapid during into the entry and their axon of to assembly prior The neurofilaments 1986). Lewis, and removed (Nixon are groups phosphate initially incorporated the of many axons, are along neurofilaments transported as However, 1987). al., et (Frappier cytoskeleton sub-axolemmal protein the important of an fodrin, their NF with modulate to interaction and the known also Sihag is of 1999; domain head Phosphorylation al., et 1991). Sihag Nixon, 1990; al., Hisanaga 2000; et al., et (Hashimoto assembly h -emnldmiso F and NFM of domains C-terminal The a itrei r phosphorylated are -internexin Journal of Cell Science rwhfcos(ie l,19b Pearson 1999b; Ca al., 2001), et al., et (Li factors to which growth respond that 2004), cascades p38 signaling al., constitute and et (JNKs) 1997) (Ackerley (MAPK14) Mushynski, kinases and N-terminal al., (Giasson et c-Jun extracellular-signal- (Veeranna 1998), kinases (Erks) as kinases regulated protein KSPxK phosphorylated such 1996; mitogen-activated Both are (MAPKs), al., sites 1995). et by KSPxxxK al., Sun and 1993; et al., proline- Veeranna (Cdk5) et by 5 (Shetty kinase phosphorylated cyclin-dependent KSPxK directed phosphorylated. are also non- motifs although are 1992), sites Lee al., et 1998; SP Xu and al., repeats 1988; et KSP al., Jaffe et on 1987; Sternberger al., occurs et domain (Geisler 1987; tail phosphorylation the Most of al., 1983). Sternberger, et for are, (Lee filaments phosphorylated highly these not reasons, unknown NFs, harbor also Sa 3260 ta. 01.Teanra phosphorylation other abnormal The 2011). from (Rudrabhatla al., et suffering disorders AD those of neurodegenerative brains and bodies the in cell patients observed in been NFs has accumulation and their of to al., phosphorylation leads et phosphorylation (Strack Aberrant PP2A NF 1997). of that of with regulation role compared minor the a increasingly only in has phosphatase PP1 protein However, and (PP1). become PP2A decreased of to neurofilament activities owing domains mainly 2011), kinases phosphorylated aging al., NF and tail et of maturation (Veeranna during activity decreases 1988). the (Pant, NFs crucial Although to exceptional the resistance their proteolysis confers also 1991). that is al., modification and et phosphorylation themselves (Hisanaga Hisanaga Tail domains microtubules 1989; Hirokawa, with NF and tail interactions the the the both between of regulate Phosphorylation can domain 1998). NF Yin al., alter 2002; al., et that et signals of (Dashiell phosphorylation role myelin possible of the mediator a by as (MAG) Friede, glycoprotein as associated and myelin well Reles as 1992; al., 1991), al., et et sheaths Mata (Hsieh 1994; myelin cells) different (the the by Ranvier generated between of nodes formed and gaps in nerves segment optic initial that the of decreased at and (de 1992) al., mice observations et Waegh is Trembler is mutant the dysmyelinating phosphorylation This phosphorylation. by NF an NF has evidenced Myelination on 1994). myelination effect al., and 2001) et al., (Nixon et (Li integrins ´ ce ta. 00.Atog h dendrites the Although 2000). al., et nchez ora fCl cec 2 (14) 125 Science Cell of Journal 2+ nlx(ie l,1999a), al., et (Li influx eraei h eeso PAadPP1 and PP2A of levels the to in attributed been decrease has a patients AD in NFs of rnpr ieiso F.Another network known NF NFs. stationary and the formation of not how of stabilization the is question regulate is kinetics remaining NFM of it transport transport domain(s) their however, which regulating in for NFs rates; many of and is transport vivo axonal NFM pathophysiology, for remain. important questions and unanswered have here biology neurofilament of reviewed understanding our studies increased the Although Perspectives of investigations. future role for challenge a interactions the remains those guiding and in phosphorylation proteins NF-interacting t and complexes), multimeric phosphatases NFs with associated different is kinases of bodies by cell and modulated phosphorylation axons in KSP (phosphorylation of topographic patients increased the regulation underlying 2008). al., AD mechanisms et with The (Deng NFM in of accompanied phosphorylation a uptake to that is due glucose in NF lower of reciprocal NFM, O-GlcNAcylation O-GlcNAcylation of decreased a phosphorylation between and observed Deng patients, AD relationship colleagues of brains and the 2011). in al., Also et Rudrabhatla (see documented) (previously patients control of brains these in of sites phosphorylation eightfold the with to compared four- approximately patients, increased was AD repeats KSP of of brains further phosphorylation which in in NFH analyses and are spectrometric NFM of mass observations by supported These al., et (Zhu 2001). JNKs ERK2 and 2004), NF and al., et of ERK1 (Veeranna levels Cdk5, elevated including to Gong kinases, and 1995; 1993), al., al., et Gong et 2005; al., et (Gong nmn,adee nesadn of desired. clearly is understanding disease dysfunction and deeper health and in function a neurofilament mind, this in With aging diseases. for neurodegenerative turnover and NF subunits, of NF relevance the of and turnover that mechanisms protein the regulate – about yet known as is – little example For have function? diseases NF that affect neurodegenerative mutations to linked NF been clear. do entirely how not also Finally, functional is vivo in neurotransmitter between receptors and The subunits interactions NF the specific transport? of for significance NF NFM with slow and of kinesin interact do phosphorylation How dynein–dynactin tails. the and heads by NFM affected are compartment-specific eietfcto of identification he rgesv ernptyi rngncmc expressing mice transgenic in neuronopathy Progressive Co 5101-5108. doi:10.1242/jcs.104729/-/DC1. http://jcs.biologists.org/lookup/suppl/ at files JPEG available as are at panels article poster this Individual of jcs.biologists.org. version for online available the is in poster downloading the of version high-resolution A months. 12 number for after PMC National release [grant in Deposited a Grant R.A.N.]. to by AG05604 Aging supported on was Institutes work This Funding al., and 2003). et 2011) al., et Sosa Nixon, Sosa (Gama Gama and (Yuan and respectively Nixon, and from Yuan permissions with adapted are network’ cytoskeletal stationary the in ‘Neurofilaments and of pathology’ ‘Neurofilament images panels microscopic poster assistance The poster. for the Peterhoff with Corrine contributions. thank additional We worthy many cite to unable were we limitations, space to Owing Acknowledgements enti,H n azrn,R A. R. subunits. NF-L Lazzarini, characteristics rodent G., and divergent human Elder, and of assembly; K., (NF) Konvicka, H. Neurofilament A., Gragerov, Weinstein, J., Carter, neurofilaments. of phosphorylation transport arm axonal C. side regulates C. Miller, chain and heavy E. Neurofilament C. J., Shaw, (2003). N., Brownlees, P. J., Leigh, H., A. B. Grierson, Anderton, mutation P., Thornhill, S., Ackerley, phenotype. nonsense recessive 54 a causes disease: in probably mutations gene K. polypeptide Charcot-Marie-Tooth Hayasaka, N., chain and Oka, light Y. H., Neurofilament Koide, Kishikawa, K., A., Saito, Honma, C., Numakura, A., Abe, References al salsmn fautpopoyainpatterns. phosphorylation adult Neurosci. of J. with establishment neurogenesis M. rat early during W. V. polypeptides W. neurofilament Schlaepfer, Lee, Q., J. and P., Trojanowski, J., M. Robert, Carden, R., J. polymerization. 29 its Eyer, Frank, modulate and and tubulin R., bind C. A. Berges, Peterson, the A., by Bocquet, assembly subunits. in peripherin NF-H and of neurofilaments NF-M disruption and cells: P. peripherin J. cultured Julien, between and J. Interactions Robertson, M., J. Beaulieu, USA Sci. neurodegeneration. Acad. and Natl. P. chain Gruss, light neurofilament accumulation and causes of TRIM2 P. ligase ubiquitin K. in Deficiency Lu, H., G., T. Lee, Alvarez-Bolado, A., Silva, Pires-da F., Ferraguti, M., A. Balastik, Brown, model. 7 transport and polymer the W. transport: P. by Baas, transport pauses. long-term neurofilament 29 of duration of the efficiency decreasing the A. Brown, and increases P. Jung, H., N. Alami, disease. neurological C. C. and Miller, and A. Al-Chalabi, sclerosis. neurofilamen lateral al. with et associated S. phospho kinase J. protein activated Perkinton, P., Waby, Thornhill, M., S., K., Ward, L., Banner, Hussain, H. Byers, J., J., Brownlees, A. S., M. 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Sosa, giant Gama squid M. the Schlief, in axon. neurofilament S., polymerized and T. tubulin E. Reese, P. A., Gallant, J. mice. Galbraith, and rats nerve sciatic of in fibers microtubules T. and neurofilaments Samorajski, to and related L. R. Friede, idn fbanseti ote7-D neurofilament 70-kDa the A. to L. spectrin protein. Pradel, neurofilament-beta- subunit brain and of F. a viable Binding Regnouf, T., in expressing Frappier, aggregates protein. fusion mice perikaryal galactosidase A. and Peterson, transgenic axons and deficient J. Eyer, hshrlto tt fnuoiaetpoen nthe vitro. on in J. proteins filaments purified neurofilament between F. interactions of J. state Leterrier, phosphorylation and J. Eyer, 739. lhie ies brain. Iqbal, disease and Alzheimer I. Grundke-Iqbal, J., T. K. Singh, X., C. Gong, al. et neurofilament A. myelin-dependent Y., conserved for growth. required axonal Uchiyama, not radial N. highly is T., repeats KSP medium Calcutt, Gotow, of J., Phosphorylation M., Crum, B., V. B., Garcia, Ellisman, J., Fujimoto, S. V., M. Shah, Rao, L., M. Garcia, neurofilament light of content. neurofilament levels subunit and (NF-L), A. neurofilament calibers, R. mid-sized axonal Lazzarini, the and decreases C., M. of Kang, V. Absence P., Lee, Bosco, H., (1998). P. Jr, Tu, L., A., V. Gourov, Friedrich, A., G. Elder, intermediate neuronal the with filaments. NR1 of subunit receptor Huganir, and NMDA motif J. R. L. O’Brien, T., repeat R. E. Fung, D., M. KSP Ehlers, the neurofilament-H. 271 and protein neurofilament domain Cleveland, and W. head G. Hart, W. Z.-S., D. Xu, L.-Y., D. Dong, disease. Alzheimer 22 in dysregulation their neurofilament- and of M I., phosphorylation Grundke-Iqbal, and X. K., C. O-GlcNAcylation Iqbal, Gong, F., and R. Liu, Brandt, B., Li, Y., myelinating Deng, phosphorylation, by transport cells. neurofilament axonal T. Schwann slow S. and of Brady, caliber, and axonal M. modulation V. Lee, Local M., S. 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Shea, intermediate perspective. network and A. neuronal neurofilament R. Nixon, proteins: ganglion stationary retinal of neurons. neurofilament axons cell a along synthesized nonuniformly distributed for newly B. evidence K. of Logvinenko, and fates A. R. Nixon, E. vivo. 16301. S. in in subunits neurons Lewis, neurofilament mammalian on and groups lateral phosphate of A. turnover amyotrophic R. of Nixon, motoneurons patients. horn sclerosis J. neurofilaments anterior D. Selkoe, phosphorylated and in of P. D. Accumulation Perl, C., (1988). Greene, G., D. Munoz, J. D. Ranvier. Fink, of node are and the epitopes at N. reduced neurofilament Kupina, Phosphorylation-dependent M., and Mata, organisation neurofilament transport. axonal disrupts J., J. C. activity Davies, C. M., Miller, PKN1 D. S., and McLoughlin, N., E. P. Banner, C. Leigh, Shaw, Y., A., Ono, L., E. Stevenson, Tudor, C., Manser, i,Y . u,Y . u . u .Y,W,D X., D. cord Wu, spinal Y., neurons. of S. motor injury Wu, Y. immune-mediated C. L., in Li, Xu, neurofilaments and Y. S., Zhang, Y. C., Guo, Yang, L., Y. Liu, cells. 3T3 motoneurons 710. C. NIH cultured transfected H. in in and extracellular Pant, of (Erk1/Erk2) activation and through regulated-kinases results repeats P. NF- KSP subunit neurofilament M. M of cascade phosphorylation Daniels, transfected stimulate S., Integrins in B. Erk2) domains Li, tail cells. and 3T3 NF-M NIH of (Erk1 Pant, phosphorylation and P. Grant, kinases G., C. Jianguo, Veeranna, H. S., B. Li, 212s-221s. , 1998-2002. , 19b.Atvto fmtgnatvtdprotein mitogen-activated of Activation (1999b). 20) odtoa FLtaseeexpression transgene NF-L Conditional (2007). elMtl Cytoskeleton Motil. Cell .Cl Biol. Cell J. ersi Lett. Neurosci. 21) lmnmidcsneurofilament induces Aluminum (2010). ri e.Ml ri Res. Brain Mol. Res. Brain .Neurosci. J. pnlCord Spinal Biochem. J. Eur. 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(1995). (2011). 159- , Hum. Mol. 25 22 J. , , h 0kasbnto erflmns al turnover Early neurofilaments. of transport. axonal subunit during on site 70-kDa phosphorylation A kinase the A. protein R. major protein a Nixon, as Ser-55 and messenger-dependent K. R. Sihag, second for Evidence kinases. by neurofilaments. of molecular regulation subunit middle the 145-kDa of mass domain head A. amino-terminal R. the Nixon, and K. R. A. Sihag, kinases. Chem. protein R. Biol. different 70-kilodalton J. the involves Nixon, of subunit domains and neurofilament distinct K. of phosphorylation specifically R. Sihag, cord spinal C. 90 H. characterization. proteins: rat and neurofilament Pant, isolation in and motifs from KSPXK T. phosphorylates W. kinase Link, cdc2-like T., K. Shetty, N-)aedpopoyae ypoenpopaae2A. phosphatase protein Neurochem. protein J. by neurofilament dephosphorylated in are (NF-H) sites C. Wang, phosphorylation H. H., kinase-5 Jaffe, Pant, T., and W. Link, J. T., K. 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