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Gene Review

Nefh  -  neurofilament, heavy polypeptide

Mus musculus

Synonyms: 200 kDa neurofilament protein, Kiaa0845, NEFH, NF-H, NF200, ...
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Disease relevance of Nefh

  • NF-H is not encountered in either the horizontal cell processes or the ganglion nerve fibers until P5 [1].
  • By 3-4 months of age, these NF-H transgenics progressively develop neurological defects and abnormal neurofilamentous swellings that are highly reminiscent of those found in amyotrophic lateral sclerosis (ALS) [2].
  • We propose that a modest up-regulation of NF-H cross-linkers can result in an impairment of neurofilament transport, causing neuronal swellings with ensuing axonopathy and muscle atrophy, a mechanism of pathogenesis pertinent to the possible etiology of ALS [2].
  • Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity [3].
  • We have found that constructs containing 5' region from -1314 to -115 exhibit a 3-5-fold higher level of NF-H promoter activity, relative to the adenovirus major late promoter (pML), in brain versus liver extracts [4].

Psychiatry related information on Nefh


High impact information on Nefh

  • First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients [7].
  • To investigate how disorganized neurofilaments might cause neurodegeneration, we examined axonal transport of newly synthesized proteins in mice that overexpress the human NF-H gene [7].
  • The transgene, regulated by NFH sequences, was expressed in projection neurons [8].
  • The phosphorylated carboxyl-terminal "tail" domains of the neurofilament (NF) subunits, NF heavy (NF-H) and NF medium (NF-M) subunits, have been proposed to regulate axon radial growth, neurofilament spacing, and neurofilament transport rate, but direct in vivo evidence is lacking [9].
  • In young mutant animals, fast axonal transport appeared to be intact, but NF-H, as well as NF-M and NF-L, accumulated in the cell bodies of peripheral sensory neurons accompanied by a reduction in sensory axon caliber [10].

Chemical compound and disease context of Nefh


Biological context of Nefh

  • Previous studies have suggested that NF number as well as the phosphorylation state of the COOH-terminal tail of the heavy neurofilament (NF-H) subunit are major determinants of axonal caliber [14].
  • Axonal transport studies carried out by the injection of [35S]methionine into spinal cord revealed an increased transport velocity of newly synthesized NF-L and NF-M proteins in motor axons of NF-H knockout mice [15].
  • The 5' regions of all three NF genes are identified as CpG islands that remain unmethylated in expressing and non-expressing tissues, although partial methylation occurs at -795 in NF-H and at -525 in NF-M [16].
  • Unlike the situation in transgenic mice expressing modest levels of human NF-H (Cote, F., J.F. Collard, and J.P. Julien. 1993. Cell. 73:35-46), even 4.5 times the normal level of wild-type mouse NF-H does not result in any overt phenotype or enhanced motor neuron degeneration or loss [17].
  • Studies on synthetic peptide analogs of KSP repeats with substitution of specific residues, known to be present in the C-terminal regions of NF-H, revealed a consensus sequence of X(S/T)PXK, characteristic of the p34cdc2 kinase substrate [18].

Anatomical context of Nefh


Associations of Nefh with chemical compounds

  • Immunoelectron microscopy investigations of the incorporation sites of NF-H labeled with biotin compounds also revealed the lateral insertion of NF-H subunits into the preexisting NF array, taking after the pattern seen in the case of NF-L [20].
  • Immunoblots of axonal proteins showed that HNE adducts are only detected in neurofilament heavy subunit (NFH) and, to a lesser extent, neurofilament medium subunit (NFM), both lysine-rich proteins, consistent with the adducts being limited to lysine residues [21].
  • Although the expression levels of phosphorylated NF-H and synaptophysin were reduced in the cerebral cortex and the hippocampus of Abeta(25-35)-injected mice, their levels in ginsenoside Rb1- and M1-treated mice were almost completely recovered up to control levels [22].
  • We examined by cell-free analyses whether or not this Triton-soluble NF-H pool was assembly-competent in cell-free analyses [23].
  • The location of this serine-rich repeat in the phosphorylated domain of NF-H indicates that it represents the major protein kinase recognition site [24].

Physical interactions of Nefh

  • Using a complementary approach, we confirmed an association of synapsin with NFs by demonstrating that immunoprecipitated synapsin I complexes contained NF-H and NF medium (160-kDa) subunits [25].

Regulatory relationships of Nefh


Other interactions of Nefh

  • The absence of the NF-M subunit resulted in a two- to threefold reduction in the caliber of large myelinated axons, whereas the lack of NF-H subunits had little effect on the radial growth of motor axons [28].
  • Using the transfected fragments, we also map the epitopes for several commonly utilised NF-H monoclonal antibodies and describe the effects that phosphorylation by cdk-5 and GSK-3alpha have on their reactivities [26].
  • There was also increased expression of phosphorylated high molecular weight neurofilament subunit (NF-H), NF-M, and MAP1B [29].
  • MAP2 (dendritic) immunostaining in the post-ischemic hippocampus showed little difference but NF200 (axonal) immunoreactivity was reduced in GFAP(-/-) [30].
  • The second conserved linkage involves human chromosome 22 and mouse chromosome 11 and contains two genetically and physically linked loci, Lif and Nfh [31].

Analytical, diagnostic and therapeutic context of Nefh


  1. The neuronal intermediate filament, alpha-internexin is transiently expressed in amacrine cells in the developing mouse retina. Chien, C.L., Liem, R.K. Exp. Eye Res. (1995) [Pubmed]
  2. Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Côté, F., Collard, J.F., Julien, J.P. Cell (1993) [Pubmed]
  3. Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase. Couillard-Després, S., Zhu, Q., Wong, P.C., Price, D.L., Cleveland, D.W., Julien, J.P. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Brain-specific enhancement of the mouse neurofilament heavy gene promoter in vitro. Schwartz, M.L., Katagi, C., Bruce, J., Schlaepfer, W.W. J. Biol. Chem. (1994) [Pubmed]
  5. Neurobehavioral characteristics of mice with modified intermediate filament genes. Lalonde, R., Strazielle, C. Reviews in the neurosciences. (2003) [Pubmed]
  6. Neuroaxonal dystrophy in experimental Creutzfeldt-Jakob disease: electron microscopical and immunohistochemical demonstration of neurofilament accumulations within affected neurites. Liberski, P.P., Budka, H., Yanagihara, R., Gajdusek, D.C. J. Comp. Pathol. (1995) [Pubmed]
  7. Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Collard, J.F., Côté, F., Julien, J.P. Nature (1995) [Pubmed]
  8. Neurofilament-deficient axons and perikaryal aggregates in viable transgenic mice expressing a neurofilament-beta-galactosidase fusion protein. Eyer, J., Peterson, A. Neuron (1994) [Pubmed]
  9. 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. Rao, M.V., Campbell, J., Yuan, A., Kumar, A., Gotow, T., Uchiyama, Y., Nixon, R.A. J. Cell Biol. (2003) [Pubmed]
  10. Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. Xia, C.H., Roberts, E.A., Her, L.S., Liu, X., Williams, D.S., Cleveland, D.W., Goldstein, L.S. J. Cell Biol. (2003) [Pubmed]
  11. Differential expression of neuroD in primary cultures of cerebral cortical neurons. Katayama, M., Mizuta, I., Sakoyama, Y., Kohyama-Koganeya, A., Akagawa, K., Uyemura, K., Ishii, K. Exp. Cell Res. (1997) [Pubmed]
  12. Cyclic AMP-dependent expression of the heavy neurofilament (NF-H) polypeptide in differentiating neuroblastoma cells. Breen, K.C., Anderton, B.H. Brain Res. Mol. Brain Res. (1990) [Pubmed]
  13. Appearance and localization of phosphorylated variants of the high molecular weight neurofilament protein in NB2a/d1 cytoskeletons during differentiation. Shea, T.B., Beermann, M.L., Nixon, R.A. Brain Res. Dev. Brain Res. (1989) [Pubmed]
  14. Requirement of heavy neurofilament subunit in the development of axons with large calibers. Elder, G.A., Friedrich, V.L., Kang, C., Bosco, P., Gourov, A., Tu, P.H., Zhang, B., Lee, V.M., Lazzarini, R.A. J. Cell Biol. (1998) [Pubmed]
  15. Disruption of the NF-H gene increases axonal microtubule content and velocity of neurofilament transport: relief of axonopathy resulting from the toxin beta,beta'-iminodipropionitrile. Zhu, Q., Lindenbaum, M., Levavasseur, F., Jacomy, H., Julien, J.P. J. Cell Biol. (1998) [Pubmed]
  16. Methylation and expression of neurofilament genes in tissues and in cell lines of the mouse. Bruce, J., Schwartz, M.L., Shneidman, P.S., Schlaepfer, W.W. Brain Res. Mol. Brain Res. (1993) [Pubmed]
  17. Neurofilament subunit NF-H modulates axonal diameter by selectively slowing neurofilament transport. Marszalek, J.R., Williamson, T.L., Lee, M.K., Xu, Z., Hoffman, P.N., Becher, M.W., Crawford, T.O., Cleveland, D.W. J. Cell Biol. (1996) [Pubmed]
  18. cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Shetty, K.T., Link, W.T., Pant, H.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  19. Antagonistic roles of neurofilament subunits NF-H and NF-M against NF-L in shaping dendritic arborization in spinal motor neurons. Kong, J., Tung, V.W., Aghajanian, J., Xu, Z. J. Cell Biol. (1998) [Pubmed]
  20. Differential dynamics of neurofilament-H protein and neurofilament-L protein in neurons. Takeda, S., Okabe, S., Funakoshi, T., Hirokawa, N. J. Cell Biol. (1994) [Pubmed]
  21. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. Wataya, T., Nunomura, A., Smith, M.A., Siedlak, S.L., Harris, P.L., Shimohama, S., Szweda, L.I., Kaminski, M.A., Avila, J., Price, D.L., Cleveland, D.W., Sayre, L.M., Perry, G. J. Biol. Chem. (2002) [Pubmed]
  22. Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, A metabolite of protopanaxadiol-type saponins. Tohda, C., Matsumoto, N., Zou, K., Meselhy, M.R., Komatsu, K. Neuropsychopharmacology (2004) [Pubmed]
  23. Triton-soluble phosphovariants of the high molecular weight neurofilament subunit from NB2a/d1 cells are assembly-competent. Implications for normal and abnormal neurofilament assembly. Shea, T.B. FEBS Lett. (1994) [Pubmed]
  24. Sequence and structure of the mouse gene coding for the largest neurofilament subunit. Julien, J.P., Côté, F., Beaudet, L., Sidky, M., Flavell, D., Grosveld, F., Mushynski, W. Gene (1988) [Pubmed]
  25. Production of monoclonal antibodies against neurofilament-associated proteins: demonstration of association with neurofilaments by a coimmunoprecipitation method. Starr, R., Xiao, J., Monteiro, M.J. J. Neurochem. (1995) [Pubmed]
  26. Phosphorylation of neurofilament heavy-chain side-arm fragments by cyclin-dependent kinase-5 and glycogen synthase kinase-3alpha in transfected cells. Bajaj, N.P., Miller, C.C. J. Neurochem. (1997) [Pubmed]
  27. Effects of truncated neurofilament proteins on the endogenous intermediate filaments in transfected fibroblasts. Chin, S.S., Macioce, P., Liem, R.K. J. Cell. Sci. (1991) [Pubmed]
  28. Disruption of type IV intermediate filament network in mice lacking the neurofilament medium and heavy subunits. Jacomy, H., Zhu, Q., Couillard-Després, S., Beaulieu, J.M., Julien, J.P. J. Neurochem. (1999) [Pubmed]
  29. Myelin-associated glycoprotein modulates expression and phosphorylation of neuronal cytoskeletal elements and their associated kinases. Dashiell, S.M., Tanner, S.L., Pant, H.C., Quarles, R.H. J. Neurochem. (2002) [Pubmed]
  30. Disturbance of hippocampal long-term potentiation after transient ischemia in GFAP deficient mice. Tanaka, H., Katoh, A., Oguro, K., Shimazaki, K., Gomi, H., Itohara, S., Masuzawa, T., Kawai, N. J. Neurosci. Res. (2002) [Pubmed]
  31. Comparative mapping of 9 human chromosome 22q loci in the laboratory mouse. Bućan, M., Gatalica, B., Nolan, P., Chung, A., Leroux, A., Grossman, M.H., Nadeau, J.H., Emanuel, B.S., Budarf, M. Hum. Mol. Genet. (1993) [Pubmed]
  32. Increased TGFbeta type II receptor expression suppresses the malignant phenotype and induces differentiation of human neuroblastoma cells. Turco, A., Scarpa, S., Coppa, A., Baccheschi, G., Palumbo, C., Leonetti, C., Zupi, G., Colletta, G. Exp. Cell Res. (2000) [Pubmed]
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