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Gene Review

NEFL  -  neurofilament, light polypeptide

Homo sapiens

Synonyms: 68 kDa neurofilament protein, CMT1F, CMT2E, NF-L, NF68, ...
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Disease relevance of NEFL


Psychiatry related information on NEFL

  • 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 [7].
  • Cytoskeletal neurofilament gene expression in brain tissue from Alzheimer's disease patients. I. Decrease in NF-L and NF-M message [8].
  • In this study, CSF levels of the light subunit of the neurofilament protein (NFL) were increased in patients with vascular dementia (VAD), AD, and frontotemporal dementia (FTD) compared with neurologically healthy individuals [9].
  • Furthermore, there was a correlation between a high level of NFL and gait disturbance, incontinence, psychometric incapability, and social dysfunction [10].

High impact information on NEFL

  • Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments [11].
  • 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 [12].
  • The relative amounts of alpha-tubulin, beta-tubulin and NF68 within axotomized perikarya increased, respectively, to 191%, 146%, and 144% of that in control perikarya isolated from the contralateral side of the spinal cord [13].
  • Alpha-tubulin, beta-tubulin, and the 68,000 molecular weight subunit of neurofilaments (NF68) decreased within the transected ventral roots to 78%, 57%, and less than 15% of control values, respectively [13].
  • Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found [14].

Chemical compound and disease context of NEFL


Biological context of NEFL

  • The NEFL gene mutation showed co-segregation with the disease phenotype and is thus most likely the disease-causing mutation [17].
  • Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21 [1].
  • We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations [1].
  • The most frequently deleted region included microsatellite (CA)n repeats markers D8S258, D8S133 and D8S259, located at 8p12-p22, while markers NEFL and LPL appeared less frequently altered [18].
  • Positive cumulative multipoint lod score of 2.51 at theta = 0.0 was obtained with markers NEFL and D8S259 [18].

Anatomical context of NEFL


Associations of NEFL with chemical compounds

  • Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline [14].
  • However, NR1 splice variants lacking the first C-terminal exon cassette (C1) failed to associate with NF-L [23].
  • To examine neurofilament (NF) aggregate-mediated sensitization of motor neurons to NMDA excitotoxicity, we examined NMDA receptor expression and the impact of NO donors (NOC12 or NOC5) or sodium cyanide (NaCN) on calcium influx and viability in dissociated motor neurons derived from wt and hNFL+/+ (NF aggregate-forming) mice [24].
  • 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) [25].
  • Cerebral cortex exhibited elevated levels of both NF-L and NF-M transcripts in DFP-treated hens throughout the period of observation [26].

Physical interactions of NEFL


Other interactions of NEFL

  • 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].
  • These results suggest a possible means of stabilization of NR1 via its association with NF-L [27].
  • NEFL to FGFR1 [28].
  • Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF [29].
  • The most frequent losses of heterozygosity (LOH) occurred at the LPL locus (46%) on chromosome 8p22 and at the D8S360 (45%) and NEFL (43%) loci on chromosome 8p21 [30].

Analytical, diagnostic and therapeutic context of NEFL


  1. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Jordanova, A., De Jonghe, P., Boerkoel, C.F., Takashima, H., De Vriendt, E., Ceuterick, C., Martin, J.J., Butler, I.J., Mancias, P., Papasozomenos, S.C.h., Terespolsky, D., Potocki, L., Brown, C.W., Shy, M., Rita, D.A., Tournev, I., Kremensky, I., Lupski, J.R., Timmerman, V. Brain (2003) [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. Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease. Niemann, A., Berger, P., Suter, U. Neuromolecular Med. (2006) [Pubmed]
  4. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. Rosengren, L.E., Karlsson, J.E., Karlsson, J.O., Persson, L.I., Wikkelsø, C. J. Neurochem. (1996) [Pubmed]
  5. 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]
  6. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Miltenberger-Miltenyi, G., Janecke, A.R., Wanschitz, J.V., Timmerman, V., Windpassinger, C., Auer-Grumbach, M., Löscher, W.N. Arch. Neurol. (2007) [Pubmed]
  7. Negative neurofilament light and tau immunostaining in frontotemporal dementia. Sjögren, M., Englund, E. Dementia and geriatric cognitive disorders. (2004) [Pubmed]
  8. Cytoskeletal neurofilament gene expression in brain tissue from Alzheimer's disease patients. I. Decrease in NF-L and NF-M message. Kittur, S., Hoh, J., Endo, H., Tourtellotte, W., Weeks, B.S., Markesbery, W., Adler, W. Journal of geriatric psychiatry and neurology. (1994) [Pubmed]
  9. Neurofilament protein levels in CSF are increased in dementia. Rosengren, L.E., Karlsson, J.E., Sjögren, M., Blennow, K., Wallin, A. Neurology (1999) [Pubmed]
  10. CSF neurofilament and glial fibrillary acidic protein in normal pressure hydrocephalus. Tullberg, M., Rosengren, L., Blomsterwall, E., Karlsson, J.E., Wikkelsö, C. Neurology (1998) [Pubmed]
  11. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Evgrafov, O.V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C.L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., Windpassinger, C., Wagner, K., Mitrovic, Z., Hilton-Jones, D., Talbot, K., Martin, J.J., Vasserman, N., Tverskaya, S., Polyakov, A., Liem, R.K., Gettemans, J., Robberecht, W., De Jonghe, P., Timmerman, V. Nat. Genet. (2004) [Pubmed]
  12. Neuronal intermediate filaments. Lee, M.K., Cleveland, D.W. Annu. Rev. Neurosci. (1996) [Pubmed]
  13. Changes in the amounts of cytoskeletal proteins within the perikarya and axons of regenerating frog motoneurons. Sinicropi, D.V., McIlwain, D.L. J. Cell Biol. (1983) [Pubmed]
  14. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Mersiyanova, I.V., Perepelov, A.V., Polyakov, A.V., Sitnikov, V.F., Dadali, E.L., Oparin, R.B., Petrin, A.N., Evgrafov, O.V. Am. J. Hum. Genet. (2000) [Pubmed]
  15. Temporal expression of neurofilament polypeptides in differentiating neuroblastoma cells. Breen, K.C., Anderton, B.H. Neuroreport (1991) [Pubmed]
  16. Intrathecal immune activation is associated with cerebrospinal fluid markers of neuronal destruction in AIDS patients. Hagberg, L., Fuchs, D., Rosengren, L., Gisslén, M. J. Neuroimmunol. (2000) [Pubmed]
  17. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. De Jonghe, P., Mersivanova, I., Nelis, E., Del Favero, J., Martin, J.J., Van Broeckhoven, C., Evgrafov, O., Timmerman, V. Ann. Neurol. (2001) [Pubmed]
  18. Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Kerangueven, F., Essioux, L., Dib, A., Noguchi, T., Allione, F., Geneix, J., Longy, M., Lidereau, R., Eisinger, F., Pébusque, M.J. Oncogene (1995) [Pubmed]
  19. The human neurofilament gene (NEFL) is located on the short arm of chromosome 8. Hurst, J., Flavell, D., Julien, J.P., Meijer, D., Mushynski, W., Grosveld, F. Cytogenet. Cell Genet. (1987) [Pubmed]
  20. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Fabrizi, G.M., Cavallaro, T., Angiari, C., Cabrini, I., Taioli, F., Malerba, G., Bertolasi, L., Rizzuto, N. Brain (2007) [Pubmed]
  21. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. Previtali, S.C., Zerega, B., Sherman, D.L., Brophy, P.J., Dina, G., King, R.H., Salih, M.M., Feltri, L., Quattrini, A., Ravazzolo, R., Wrabetz, L., Monaco, A.P., Bolino, A. Hum. Mol. Genet. (2003) [Pubmed]
  22. Neurofilaments of Klotho, the mutant mouse prematurely displaying symptoms resembling human aging. Uchida, A., Komiya, Y., Tashiro, T., Yorifuji, H., Kishimoto, T., Nabeshima, Y., Hisanaga, S. J. Neurosci. Res. (2001) [Pubmed]
  23. Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. Ehlers, M.D., Fung, E.T., O'Brien, R.J., Huganir, R.L. J. Neurosci. (1998) [Pubmed]
  24. Loss of nitric oxide-mediated down-regulation of NMDA receptors in neurofilament aggregate-bearing motor neurons in vitro: Implications for motor neuron disease. Sanelli, T., Strong, M.J. Free Radic. Biol. Med. (2007) [Pubmed]
  25. 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]
  26. Enhanced mRNA expression of neurofilament subunits in the brain and spinal cord of diisopropyl phosphorofluoridate-treated hens. Gupta, R.P., Lin, W.W., Abou-Donia, M.B. Biochem. Pharmacol. (1999) [Pubmed]
  27. Neurofilament-light increases the cell surface expression of the N-methyl-D-aspartate receptor and prevents its ubiquitination. Ratnam, J., Teichberg, V.I. J. Neurochem. (2005) [Pubmed]
  28. Integrated map of the chromosome 8p12-p21 region, a region involved in human cancers and Werner syndrome. Imbert, A., Chaffanet, M., Essioux, L., Noguchi, T., Adélaïde, J., Kerangueven, F., Le Paslier, D., Bonaïti-Pellié, C., Sobol, H., Birnbaum, D., Pébusque, M.J. Genomics (1996) [Pubmed]
  29. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Fabrizi, G.M., Cavallaro, T., Angiari, C., Bertolasi, L., Cabrini, I., Ferrarini, M., Rizzuto, N. Neurology (2004) [Pubmed]
  30. Homozygous deletions at 8p22 and 8p21 in prostate cancer implicate these regions as the sites for candidate tumor suppressor genes. Kagan, J., Stein, J., Babaian, R.J., Joe, Y.S., Pisters, L.L., Glassman, A.B., von Eschenbach, A.C., Troncoso, P. Oncogene (1995) [Pubmed]
  31. Origin of the two mRNA species for the human neurofilament light gene. Beaudet, L., Charron, G., Julien, J.P. Biochem. Cell Biol. (1992) [Pubmed]
  32. Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. Yoshihara, T., Yamamoto, M., Hattori, N., Misu, K., Mori, K., Koike, H., Sobue, G. J. Peripher. Nerv. Syst. (2002) [Pubmed]
  33. Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models. Kabzińska, D., Perez-Olle, R., Goryunov, D., Drac, H., Ryniewicz, B., Hausmanowa-Petrusewicz, I., Kochański, A., Liem, R.K. J. Peripher. Nerv. Syst. (2006) [Pubmed]
  34. 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]
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