Neurofilament light polypeptide explained

Neurofilament light polypeptide, also known as neurofilament light chain, abbreviated to NF-L or Nfl and with the HGNC name NEFL is a member of the intermediate filament protein family. This protein family consists of over 50 human proteins divided into 5 major classes, the Class I and II keratins, Class III vimentin, GFAP, desmin and the others, the Class IV neurofilaments and the Class V nuclear lamins. There are four major neurofilament subunits, NF-L, NF-M, NF-H and α-internexin. These form heteropolymers which assemble to produce 10nm neurofilaments which are only expressed in neurons where they are major structural proteins, particularly concentrated in large projection axons. Axons are particularly sensitive to mechanical and metabolic compromise and as a result axonal degeneration is a significant problem in many neurological disorders. The detection of neurofilament subunits in CSF and blood has therefore become widely used as a biomarker of ongoing axonal compromise. The NF-L protein is encoded by the NEFL gene.^{[1] [2]} Neurofilament light chain is a biomarker that can be measured with immunoassays in cerebrospinal fluid and plasma and reflects axonal damage in a wide variety of neurological disorders.^{[3] [4]} It is a useful marker for disease monitoring in amyotrophic lateral sclerosis,^[5] multiple sclerosis,^[6] Alzheimer's disease,^{[7] [8]} and more recently Huntington's disease.^[9] It is also promising marker for follow-up of patients with brain tumors.^[10] Higher levels of blood or CSF NF-L have been associated with increased mortality, as would be expected as release of this protein reflects ongoing axonal loss.^[11] Recent work performed as a collaboration between EnCor Biotechnology Inc. and the University of Florida showed that the NF-L antibodies employed in the most widely used NF-L assays are specific for cleaved forms of NF-L generated by proteolysis induced by cell death.^[12] Methods used in different studies for NfL measurement are sandwich enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence, and high-sensitive single molecule array (SIMOA).^[13]

Neurofilament assembly and structure

It is associated with Charcot–Marie–Tooth disease 1F and 2E.

Interactions

Neurofilament light polypeptide has been shown to interact with:

• MAP2,^[14]
• Protein kinase N1,^[15] and
• TSC1.^[16]

References

Further reading

• Hirokawa N, Takeda S . Gene targeting studies begin to reveal the function of neurofilament proteins . The Journal of Cell Biology . 143 . 1 . 1–4 . October 1998 . 9763415 . 2132816 . 10.1083/jcb.143.1.1 .
• Beaudet L, Charron G, Julien JP . Origin of the two mRNA species for the human neurofilament light gene . Biochemistry and Cell Biology . 70 . 5 . 279–284 . May 1992 . 1497855 . 10.1139/o92-044 .
• Chin SS, Liem RK . Expression of rat neurofilament proteins NF-L and NF-M in transfected non-neuronal cells . European Journal of Cell Biology . 50 . 2 . 475–490 . December 1989 . 2516804 .
• Julien JP, Grosveld F, Yazdanbaksh K, Flavell D, Meijer D, Mushynski W . The structure of a human neurofilament gene (NF-L): a unique exon-intron organization in the intermediate filament gene family . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 909 . 1 . 10–20 . June 1987 . 3034332 . 10.1016/0167-4781(87)90041-8 . free . 1765/2408 .
• Hurst J, Flavell D, Julien JP, Meijer D, Mushynski W, Grosveld F . The human neurofilament gene (NEFL) is located on the short arm of chromosome 8 . Cytogenetics and Cell Genetics . 45 . 1 . 30–32 . 1987 . 3036423 . 10.1159/000132421 . free . 1765/2414 .
• Frappier T, Regnouf F, Pradel LA . Binding of brain spectrin to the 70-kDa neurofilament subunit protein . European Journal of Biochemistry . 169 . 3 . 651–657 . December 1987 . 3121319 . 10.1111/j.1432-1033.1987.tb13657.x . free .
• Nomata Y, Watanabe T, Wada H . Highly acidic proteins from human brain: purification and properties of Glu-50 protein . Journal of Biochemistry . 93 . 3 . 825–831 . March 1983 . 6135695 . 10.1093/jb/93.3.825 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Pospelov VA, Pospelova TV, Julien JP . AP-1 and Krox-24 transcription factors activate the neurofilament light gene promoter in P19 embryonal carcinoma cells . Cell Growth & Differentiation . 5 . 2 . 187–196 . February 1994 . 8180132 .
• Dong DL, Xu ZS, Chevrier MR, Cotter RJ, Cleveland DW, Hart GW . Glycosylation of mammalian neurofilaments. Localization of multiple O-linked N-acetylglucosamine moieties on neurofilament polypeptides L and M . The Journal of Biological Chemistry . 268 . 22 . 16679–16687 . August 1993 . 8344946 . 10.1016/S0021-9258(19)85471-6 . free .
• Charron G, Guy LG, Bazinet M, Julien JP . Multiple neuron-specific enhancers in the gene coding for the human neurofilament light chain . The Journal of Biological Chemistry . 270 . 51 . 30604–30610 . December 1995 . 8530496 . 10.1074/jbc.270.51.30604 . free .
• Mukai H, Toshimori M, Shibata H, Kitagawa M, Shimakawa M, Miyahara M, Sunakawa H, Ono Y . PKN associates and phosphorylates the head-rod domain of neurofilament protein . The Journal of Biological Chemistry . 271 . 16 . 9816–9822 . April 1996 . 8621664 . 10.1074/jbc.271.16.9816 . free.
• Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C . Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF . Journal of Neurochemistry . 67 . 5 . 2013–2018 . November 1996 . 8863508 . 10.1046/j.1471-4159.1996.67052013.x . 36897027 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Athlan ES, Mushynski WE . Heterodimeric associations between neuronal intermediate filament proteins . The Journal of Biological Chemistry . 272 . 49 . 31073–31078 . December 1997 . 9388258 . 10.1074/jbc.272.49.31073 . free .
• Ehlers MD, Fung ET, O'Brien RJ, Huganir RL . Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments . The Journal of Neuroscience . 18 . 2 . 720–730 . January 1998 . 9425014 . 6792537 . 10.1523/JNEUROSCI.18-02-00720.1998 .
• Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV . A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene . American Journal of Human Genetics . 67 . 1 . 37–46 . July 2000 . 10841809 . 1287099 . 10.1086/302962 .
• De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, Evgrafov O, Timmerman V . Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E . Annals of Neurology . 49 . 2 . 245–249 . February 2001 . 11220745 . 10.1002/1531-8249(20010201)49:2<245::AID-ANA45>3.0.CO;2-A . 28966753 .
• Shaw G, Madorsky I, Li Y, Wang Y, Rana S, Jorgensen M, Fuller DD . Uman Type Neurofilament Light Antibodies Are Effective Reagents for the Imaging of Neurodegeneration . Brain Communications . April 2023 . 5 . 2 . fcad067 . 37091583 . 10.1093/braincomms/fcad067. free . 10120172 .

External links

• Book: Bird, Thomas D . Charcot-Marie-Tooth Neuropathy Type 1 . NBK1205 . https://www.ncbi.nlm.nih.gov/books/NBK1205/ . Pagon RA, Bird TD, Dolan CR . GeneReviews . 26 March 2015 . University of Washington, Seattle . Seattle WA . 20301295 . . etal.
• Book: Bird, Thomas D . Charcot-Marie-Tooth Neuropathy Type 2 . Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . NBK1285 . 30 January 2014 . University of Washington, Seattle . 20301462 . In
• Book: Peter . De Jonghe . Albena K . Jordanova . 2011-10-27 . Charcot-Marie-Tooth Neuropathy Type 2E/1F . Charcot-Marie-Tooth Neuropathy Type 2E/1F – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . University of Washington, Seattle . 20301366 . NBK1187 . In

Notes and References

1. Miltenberger-Miltenyi G, Janecke AR, Wanschitz JV, Timmerman V, Windpassinger C, Auer-Grumbach M, Löscher WN . Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene . Archives of Neurology . 64 . 7 . 966–970 . July 2007 . 17620486 . 10.1001/archneur.64.7.966 .
2. Web site: Entrez Gene: NEFL neurofilament, light polypeptide 68kDa.
3. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J . Neurofilaments as biomarkers in neurological disorders . Nature Reviews. Neurology . 14 . 10 . 577–589 . October 2018 . 30171200 . 10.1038/s41582-018-0058-z . neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. ... Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. . 52140127 .
4. Thompson AG, Mead SH . Review: Fluid biomarkers in the human prion diseases . Molecular and Cellular Neurosciences . 97 . 81–92 . June 2019 . 30529227 . 10.1016/j.mcn.2018.12.003 . The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. . 54437514 .
5. Xu Z, Henderson RD, David M, McCombe PA . Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis . PLOS ONE . 11 . 10 . e0164625 . 2016 . 27732645 . 5061412 . 10.1371/journal.pone.0164625 . NF heavy and light chain levels have potential use as a marker of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression. . free . 2016PLoSO..1164625X .
6. Cai L, Huang J . Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study . Neuropsychiatric Disease and Treatment . 14 . 2241–2254 . 2018 . 30214214 . 6126505 . 10.2147/NDT.S173280 . NFL chain has significantly increased in MS patients, which substantially strengthens the clinical evidence of the NFL in MS. The NFL may be used as a prognostic biomarker to monitor disease progression, disease activity, and treatment efficacy in the future. . free .
7. Zetterberg H, Schott JM . Biomarkers for Alzheimer's disease beyond amyloid and tau . Nature Medicine . 25 . 2 . 201–203 . February 2019 . 30728536 . 10.1038/s41591-019-0348-z . 59607046 .
8. Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TL, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M . Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease . Nature Medicine . 25 . 2 . 277–283 . February 2019 . 30664784 . 6367005 . 10.1038/s41591-018-0304-3 .
9. Niemelä V, Landtblom AM, Blennow K, Sundblom J . Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease? . PLOS ONE . 12 . 2 . e0172762 . 27 February 2017 . 28241046 . 5328385 . 10.1371/journal.pone.0172762 . free . 2017PLoSO..1272762N .
10. Arslan B, Ayhan Arslan G, Tuncer A, Karabudak R, Sepici Dinçel A . Evaluation of cerebrospinal fluid neurofilament light chain levels in multiple sclerosis and non-demyelinating diseases of the central nervous system: clinical and biochemical perspective . Bosnian Journal of Basic Medical Sciences . April 2022 . 22 . 5 . 699–706 . 35490364 . 10.17305/bjbms.2021.7326 . 9519158 . 248478048 .
11. A neuronal blood marker is associated with mortality in old age . 2021 . 10.1038/s43587-021-00028-4 . February 11, 2021. Kaeser . Stephan A. . Lehallier . Benoit . Thinggaard . Mikael . Häsler . Lisa M. . Apel . Anja . Bergmann . Carina . Berdnik . Daniela . Jeune . Bernard . Christensen . Kaare . Grönke . Sebastian . Partridge . Linda . Wyss-Coray . Tony . Mengel-From . Jonas . Jucker . Mathias . Nature Aging . 1 . 2 . 218–225 . 37118632 . 234008316 .
12. Shaw G, Madorsky I, Li Y, Wang Y, Rana S, Jorgensen M, Fuller DD . Uman Type Neurofilament Light Antibodies Are Effective Reagents for the Imaging of Neurodegeneration . Brain Communications . April 2023 . 37091583 . 10.1093/braincomms/fcad067.
13. Arslan . Burak . Arslan . Gökçe Ayhan . Tuncer . Aslı . Karabudak . Rana . Dinçel . Aylin Sepici . 2022-09-16 . Evaluation of cerebrospinal fluid neurofilament light chain levels in multiple sclerosis and non-demyelinating diseases of the central nervous system: clinical and biochemical perspective . Bosnian Journal of Basic Medical Sciences . en . 22 . 5 . 699–706 . 10.17305/bjbms.2021.7326 . 35490364 . 2831-090X. 9519158 .
14. Frappier T, Stetzkowski-Marden F, Pradel LA . Interaction domains of neurofilament light chain and brain spectrin . The Biochemical Journal . 275 . 2 . 521–527 . April 1991 . 1902666 . 1150082 . 10.1042/bj2750521 .
15. Mukai H, Toshimori M, Shibata H, Kitagawa M, Shimakawa M, Miyahara M, Sunakawa H, Ono Y . PKN associates and phosphorylates the head-rod domain of neurofilament protein . The Journal of Biological Chemistry . 271 . 16 . 9816–9822 . April 1996 . 8621664 . 10.1074/jbc.271.16.9816 . free.
16. Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, Ramesh V . The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton . The Journal of Biological Chemistry . 277 . 46 . 44180–44186 . November 2002 . 12226091 . 10.1074/jbc.M207211200 . free .