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Gene Review

NEFH  -  neurofilament, heavy polypeptide

Homo sapiens

Synonyms: 200 kDa neurofilament protein, KIAA0845, NF-H, NFH, Neurofilament heavy polypeptide, ...
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Disease relevance of NEFH

  • FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus [1].
  • RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion [1].
  • Previous studies demonstrated that transgenic mice overexpressing human neurofilament heavy (hNF-H) protein develop a progressive motor neuron disease characterized by the perikaryal accumulations of neurofilaments resembling those found in amyotrophic lateral sclerosis (ALS) [2].
  • We observed no differences between ALS and normal controls in the physicochemical properties of NFH in Triton X-100 insoluble protein fractions, with respect to migration patterns on 2D-iso electrofocusing (IEF) gels, the rate of Escherichia coli alkaline phosphatase mediated dephosphorylation, or the rate of calpain-mediated proteolysis [3].
  • Northern blot analysis revealed a single RNA band of 4800 bp for NFH in normal brain but two RNA species of 4800 and 3800 bp in both neuroblastoma and adrenal cells, confirming their common origin [4].

Psychiatry related information on NEFH

  • We investigated the immunohistochemical stainability of phosphorylated tau and the light (NFL), intermediate (NFM), and heavy (NFH) neurofilament proteins in postmortem brain tissue from 8 patients with frontotemporal dementia (FTD), for comparison with 6 patients with Alzheimer's disease (AD), and 6 normal controls [5].
  • Neurofilament proteins NF-L, NF-M and NF-H in brain of patients with Down syndrome and Alzheimer's disease [6].
  • This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans [7].
  • Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities [8].
  • By immunohistochemical techniques, the accumulation of 200 kDa neurofilament protein was demonstrated in affected neurites in human CJD [9].

High impact information on NEFH

  • Assembled as obligate heteropolymers requiring NF-L and substoichiometric amounts of NF-M and/or NF-H, NF investment into axons is essential for establishment of axonal caliber, itself a key determinant of conduction velocity [10].
  • Thus, phosphorylation of NFH slows neurofilament transport, and this is due to increased pausing in neurofilament movement [11].
  • The protein segment on the carboxy-terminal side of the human NF-H rod is uniquely long (greater than 600 amino acids) compared to other IF proteins and is highly charged (greater than 24% Glu, greater than 25% Lys), rich in proline (greater than 12%) and impoverished in cysteine, methionine and aromatic amino acids [12].
  • Genomic clones for the largest human neurofilament protein (NF-H) were isolated, the intron/exon boundaries mapped and the entire protein-coding regions (exons) sequenced [12].
  • Together with the recent identification of the serine in KSP as the main target for NF-directed protein kinases in vivo, this repetitive character explains the massive phosphorylation of the NF-H subunit that can occur in axons [12].

Chemical compound and disease context of NEFH

  • Findings in the present study suggest that atrophy, that is, the reduction in axonal calibre and paranodal demyelination, seen in leprous nerves may result from dephosphorylation of NF-H and NF-M proteins [13].

Biological context of NEFH

  • Previously, we have demonstrated polymorphism in the C-terminal region of the human NEFH: an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif [14].
  • Two loci, D22S32 and NEFH, are linked to the NF2 locus at 0% recombination (lod scores of 6.03 and 4.28, respectively) [15].
  • To investigate whether the L/S genotypes of the NEFH gene are associated with MND, we studied the frequency of L and S alleles in sporadic MND patients and a control population from Moscow [16].
  • Since it may be hypothesized that mutations in the phosphorylated region are a basis for neuropathological conditions, and since regions of the human genome containing repeat motifs have been demonstrated to be significantly polymorphic, we undertook to identify and characterize polymorphism in this region of the human NEFH gene [17].
  • The heavy neurofilament subunit (NFH) tail is composed of a repeating amino acid motif, usually X-lysine-serine-proline-Y-lysine (XKSPYK), where X is a single amino acid and Y is one to three amino acids [18].

Anatomical context of NEFH


Associations of NEFH with chemical compounds

  • However, NF-H, NF-M, and NF-L were expressed throughout the cell cycle in dual parameter studies of D283 cells labeled with an antibody and propidium iodide [23].
  • Cleavage at cysteine and chymotrypsin digestion were applied to two human neurofilament (NF) subunits, low- and high-molecular-weight NF (NF-L and NF-H), to locate the regions reacting with Bodian's silver stain and with several monoclonal antibodies, including NF-specific antibodies and one that recognizes all intermediate filaments (anti-IFA) [24].
  • When cytoskeleton preparations were exposed to aluminum salt concentrations of 100 microM or higher, proportions of NF-M and NF-H formed urea-insoluble complexes of high apparent molecular mass, which were also resistant to proteolysis by calpain [25].
  • Upon differentiation of SHSY5Y cells with retinoic acid, we found that the phosphorylation of high molecular mass (NF-H) and medium molecular mass (NF-M) NFs increased, whereas the CDK-5 protein level and kinase activity were unaffected [26].
  • Following a 15 min pulse radiolabeling, NF-H isoforms migrating from approximately 160-200 kDa, NF-M isoforms migrating from approximately 97 k-145 Da, and a single 70 kDa NF-L isoform were readily detectable within Triton-soluble fractions from both undifferentiated and differentiated cells [27].

Enzymatic interactions of NEFH

  • One hour after death, enhanced perikaryal immunostaining of NF-M and both phosphorylated and nonphosphorylated NF-H epitopes was observed throughout the hippocampal formation [28].
  • These results demonstrate that CDK-5 is a major proline-directed kinase phosphorylating the human NF-H tail domain [26].

Regulatory relationships of NEFH

  • The low (NF-L) and middle (NF-M) molecular weight (Mr) neurofilament (NF) subunits are expressed before the high (NF-H) Mr NF subunit in embryonic neurons [23].

Other interactions of NEFH

  • In hNF-H transgenic mice, the additional hNF-L led to reduction of perikaryal swellings, relief of axonal transport defect and restoration of axonal radial growth [2].
  • Antibodies to the HNK-1 and Gal(beta 1-3)GalNAc epitopes, which have been implicated in human autoimmune neuropathy and motor neuron disease, respectively, immunostained the surface of the neuroblastoma cells, and antibodies to the 200 kDa high molecular weight neurofilament protein (NFH) immunostained the cytoplasm and cell processes [4].
  • In this study, an identified cyclin-dependent kinase 5 (cdk5), isolated from nervous tissue, has been shown to phosphorylate the human NF-H (hNF-H) and affects its electrophoretic mobility [29].
  • Except for these Lys-Ser-Pro motifs, there is surprisingly little structural similarity between the squid NF-220 protein and mammalian NF-M and NF-H proteins [30].
  • We screened the KSP repeat region of the NEFH gene in 117 unrelated individuals who inherited familial amyotrophic lateral sclerosis as an autosomal trait but who do not have the mutation in the SOD1 locus, and we found no variants in any individual [31].

Analytical, diagnostic and therapeutic context of NEFH

  • Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32 [1].
  • Phosphopeptides and the phosphorylated motifs characterized by liquid chromatography tandem mass spectroscopy (LC/MS/MS) analysis demonstrated that all the phosphorylated residues found in ALS NFH were also found to be phosphorylated in normal human NFH samples [3].
  • Fluorescence in situ hybridization and pulsed field gel electrophoresis confirm the presence of a 700kb deletion which includes the neurofilament heavy chain subunit gene locus (NEFH), D22S268, NF2 and the putative MEN gene [32].
  • In order to isolate proteins that bind NF, we first expressed the carboxyl-terminal tail domain of the mouse high-molecular-weight NF subunit (NF-H) as a fusion protein in bacteria and then used this portion of NF-H as a ligand in affinity chromatography [33].
  • Electron microscopy observations revealed that parallel arrays of 10 nm filaments with frequent crossbridges between adjacent filaments were formed in the cytoplasm of Sf9 cells infected with the recombinant virus that co-expressed NF-L and NF-H [34].


  1. A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus. Watson, C.J., Gaunt, L., Evans, G., Patel, K., Harris, R., Strachan, T. Hum. Mol. Genet. (1993) [Pubmed]
  2. Extra neurofilament NF-L subunits rescue motor neuron disease caused by overexpression of the human NF-H gene in mice. Meier, J., Couillard-Després, S., Jacomy, H., Gravel, C., Julien, J.P. J. Neuropathol. Exp. Neurol. (1999) [Pubmed]
  3. Phosphorylation state of the native high-molecular-weight neurofilament subunit protein from cervical spinal cord in sporadic amyotrophic lateral sclerosis. Strong, M.J., Strong, W.L., Jaffe, H., Traggert, B., Sopper, M.M., Pant, H.C. J. Neurochem. (2001) [Pubmed]
  4. Autoantigens in human neuroblastoma cells. Srinivasan, J., Hays, A.P., Thomas, F.P., Sadiq, S.A., Barth, K.H., Liem, R., Mena, M.A., DeYebenes, J.G., Latov, N. J. Neuroimmunol. (1990) [Pubmed]
  5. Negative neurofilament light and tau immunostaining in frontotemporal dementia. Sjögren, M., Englund, E. Dementia and geriatric cognitive disorders. (2004) [Pubmed]
  6. Neurofilament proteins NF-L, NF-M and NF-H in brain of patients with Down syndrome and Alzheimer's disease. Bajo, M., Yoo, B.C., Cairns, N., Gratzer, M., Lubec, G. Amino Acids (2001) [Pubmed]
  7. Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. Ferrer-Alcón, M., La Harpe, R., Guimón, J., García-Sevilla, J.A. Neuropsychopharmacology (2003) [Pubmed]
  8. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Jyonouchi, H., Geng, L., Ruby, A., Zimmerman-Bier, B. Neuropsychobiology (2005) [Pubmed]
  9. How do neurons degenerate in transmissible spongiform encephalopathies? Liberski, P.P. Mol. Chem. Neuropathol. (1996) [Pubmed]
  10. Neuronal intermediate filaments. Lee, M.K., Cleveland, D.W. Annu. Rev. Neurosci. (1996) [Pubmed]
  11. Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments. Ackerley, S., Thornhill, P., Grierson, A.J., Brownlees, J., Anderton, B.H., Leigh, P.N., Shaw, C.E., Miller, C.C. J. Cell Biol. (2003) [Pubmed]
  12. The structure and organization of the human heavy neurofilament subunit (NF-H) and the gene encoding it. Lees, J.F., Shneidman, P.S., Skuntz, S.F., Carden, M.J., Lazzarini, R.A. EMBO J. (1988) [Pubmed]
  13. Alterations in neurofilament protein(s) in human leprous nerves: morphology, immunohistochemistry and Western immunoblot correlative study. Save, M.P., Shetty, V.P., Shetty, K.T., Antia, N.H. Neuropathol. Appl. Neurobiol. (2004) [Pubmed]
  14. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Figlewicz, D.A., Krizus, A., Martinoli, M.G., Meininger, V., Dib, M., Rouleau, G.A., Julien, J.P. Hum. Mol. Genet. (1994) [Pubmed]
  15. Presymptomatic diagnosis for neurofibromatosis 2 with chromosome 22 markers. Ruttledge, M.H., Narod, S.A., Dumanski, J.P., Parry, D.M., Eldridge, R., Wertelecki, W., Parboosingh, J., Faucher, M.C., Lenoir, G.M., Collins, V.P. Neurology (1993) [Pubmed]
  16. Analysis of heavy neurofilament subunit gene polymorphism in Russian patients with sporadic motor neuron disease (MND). Skvortsova, V., Shadrina, M., Slominsky, P., Levitsky, G., Kondratieva, E., Zherebtsova, A., Levitskaya, N., Alekhin, A., Serdyuk, A., Limborska, S. Eur. J. Hum. Genet. (2004) [Pubmed]
  17. Polymorphism in the multi-phosphorylation domain of the human neurofilament heavy-subunit-encoding gene. Figlewicz, D.A., Rouleau, G.A., Krizus, A., Julien, J.P. Gene (1993) [Pubmed]
  18. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Al-Chalabi, A., Andersen, P.M., Nilsson, P., Chioza, B., Andersson, J.L., Russ, C., Shaw, C.E., Powell, J.F., Leigh, P.N. Hum. Mol. Genet. (1999) [Pubmed]
  19. In vivo and in vitro phosphorylation at Ser-493 in the glutamate (E)-segment of neurofilament-H subunit by glycogen synthase kinase 3beta. Sasaki, T., Taoka, M., Ishiguro, K., Uchida, A., Saito, T., Isobe, T., Hisanaga, S. J. Biol. Chem. (2002) [Pubmed]
  20. Altered ionic conductances in axons of transgenic mouse expressing the human neurofilament heavy gene: A mouse model of amyotrophic lateral sclerosis. Kriz, J., Meier, J., Julien, J.P., Padjen, A.L. Exp. Neurol. (2000) [Pubmed]
  21. Decreased expression of NEFH and PCP4/PEP19 in the prefrontal cortex of alcoholics. Iwamoto, K., Bundo, M., Yamamoto, M., Ozawa, H., Saito, T., Kato, T. Neurosci. Res. (2004) [Pubmed]
  22. Co-expression of low molecular weight neurofilament protein and glial fibrillary acidic protein in established human glioma cell lines. Tlhyama, T., Lee, V.M., Trojanowski, J.Q. Am. J. Pathol. (1993) [Pubmed]
  23. Phosphate-dependent and independent neurofilament protein epitopes are expressed throughout the cell cycle in human medulloblastoma (D283 MED) cells. Trojanowski, J.Q., Kelsten, M.L., Lee, V.M. Am. J. Pathol. (1989) [Pubmed]
  24. Binding of Bodian's silver and monoclonal antibodies to defined regions of human neurofilament subunits: Bodian's silver reacts with a highly charged unique domain of neurofilaments. Autilio-Gambetti, L., Crane, R., Gambetti, P. J. Neurochem. (1986) [Pubmed]
  25. Aluminum inhibits calpain-mediated proteolysis and induces human neurofilament proteins to form protease-resistant high molecular weight complexes. Nixon, R.A., Clarke, J.F., Logvinenko, K.B., Tan, M.K., Hoult, M., Grynspan, F. J. Neurochem. (1990) [Pubmed]
  26. CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells. Sharma, M., Sharma, P., Pant, H.C. J. Neurochem. (1999) [Pubmed]
  27. Differential synthesis and cytoskeletal deposition of neurofilament subunits before and during axonal outgrowth in NB2a/d1 cells: evidence that segregation of phosphorylated subunits within the axonal cytoskeleton involves selective deposition. Shea, T.B. J. Neurosci. Res. (1995) [Pubmed]
  28. Perikaryal accumulation and proteolysis of neurofilament proteins in the post-mortem rat brain. Geddes, J.W., Bondada, V., Tekirian, T.L., Pang, Z., Siman, R.G. Neurobiol. Aging (1995) [Pubmed]
  29. Phosphorylation of human high molecular weight neurofilament protein (hNF-H) by neuronal cyclin-dependent kinase 5 (cdk5). Pant, A.C., Veeranna, n.u.l.l., Pant, H.C., Amin, N. Brain Res. (1997) [Pubmed]
  30. A high-molecular-weight squid neurofilament protein contains a lamin-like rod domain and a tail domain with Lys-Ser-Pro repeats. Way, J., Hellmich, M.R., Jaffe, H., Szaro, B., Pant, H.C., Gainer, H., Battey, J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  31. Analysis of the KSP repeat of the neurofilament heavy subunit in familiar amyotrophic lateral sclerosis. Rooke, K., Figlewicz, D.A., Han, F.Y., Rouleau, G.A. Neurology (1996) [Pubmed]
  32. Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus. Sanson, M., Marineau, C., Desmaze, C., Lutchman, M., Ruttledge, M., Baron, C., Narod, S., Delattre, O., Lenoir, G., Thomas, G. Hum. Mol. Genet. (1993) [Pubmed]
  33. Identification and characterization of a novel (115 kDa) neurofilament-associated kinase. Xiao, J., Monteiro, M.J. J. Neurosci. (1994) [Pubmed]
  34. The C-terminal tail domain of neurofilament protein-H (NF-H) forms the crossbridges and regulates neurofilament bundle formation. Chen, J., Nakata, T., Zhang, Z., Hirokawa, N. J. Cell. Sci. (2000) [Pubmed]
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