Biology:Neurofilament light polypeptide

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Short description: Protein-coding gene in the species Homo sapiens

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Neurofilament light polypeptide is a protein that in humans is encoded by the NEFL gene.[1]

Structure

Neurofilament light polypeptide 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 10 nm neurofilaments which are only expressed in neurons where they are major structural proteins, particularly concentrated in large projection axons. The NF-L protein is encoded by the NEFL gene.[2][1]

Function

These neurofilament heteropolymers assemble into the cytoskeleton of axons, where they provide structural support and help regulate axonal diameter and conduction velocity. Axons are particularly sensitive to mechanical and metabolic compromise and as a result axonal degeneration is a significant problem in many neurological disorders. 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]

Measurement

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.[4] Methods used in different studies for NfL measurement are sandwich enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence, and high-sensitive single molecule array (SIMOA).[5]

Clinical significance

The detection of neurofilament subunits in CSF and blood has become widely used as a biomarker of ongoing axonal compromise. It is a useful marker for disease monitoring in amyotrophic lateral sclerosis,[6] multiple sclerosis,[7] Alzheimer's disease,[8][9] and more recently Huntington's disease.[10] It is also a promising marker for follow-up of patients with brain tumors.[11] 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.[12]

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

Neurofilament assembly

Rat brain cells grown in tissue culture and stained, in green, with an antibody to neurofilament subunit NF-L, which reveals a large neuron. The culture was stained in red for α-internexin, which in this culture is found in neuronal stem cells surrounding the large neuron.
A formalin-fixed and paraffin-embedded section of the human cerebellum is stained with an antibody specific to NF-L, visualized with a brown dye. Cell nuclei are counterstained with a blue dye. The nucleus-rich region on the left side corresponds to the granular layer, while the region on the right represents the molecular layer. The antibody binds to the processes of basket cells, the parallel fiber axons, the perikarya (cell bodies) of Purkinje cells, and various other axons.

Neurofilament light polypeptide (NF-L) is a key structural component of the neuronal cytoskeleton, assembling into neurofilaments along with other intermediate filament proteins such as NF-M, NF-H, and α-internexin.[13][14] These proteins form obligate heteropolymers that organize into 10 nm diameter filaments,[13][14] which are selectively expressed in neurons and are particularly concentrated in axons[9]. Neurofilaments provide essential structural support, help maintain axonal diameter,[15][14] and contribute to the efficient conduction of nerve impulses.[15]

The localization and organization of NF-L in neurons can be visualized using immunohistochemical techniques. In tissue culture preparations of rat brain cells, antibodies specific to NF-L label large neurons prominently in green, revealing their extensive cytoskeletal architecture.[16] In the same cultures, staining for α-internexin in red highlights surrounding neuronal stem cells, indicating the differential expression of these intermediate filament proteins during neural development and differentiation.[14]

In histological sections of human brain tissue, NF-L can also be visualized using immunostaining. For example, in formalin-fixed and paraffin-embedded sections of the human cerebellum, an antibody specific to NF-L reveals its presence throughout various neuronal compartments[7]. The brown-stained antibody binding highlights the axonal processes of basket cells, the parallel fibers of granule cells,[17][14] the perikarya of Purkinje cells,[17] and other axonal elements. Counterstaining with a blue dye allows for the visualization of cell nuclei, delineating the granular layer on the left side of the section and the molecular layer on the right.[17] These staining patterns underscore the widespread and structurally critical role of NF-L in both developing and mature neurons.[15][14]

Interactions

Neurofilament light polypeptide has been shown to interact with:

References

  1. ↑ 1.0 1.1 "Entrez Gene: NEFL neurofilament, light polypeptide 68kDa". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4747. 
  2. ↑ 2.0 2.1 "Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene". Archives of Neurology 64 (7): 966–970. July 2007. doi:10.1001/archneur.64.7.966. PMID 17620486. 
  3. ↑ "Neurofilaments as biomarkers in neurological disorders". Nature Reviews. Neurology 14 (10): 577–589. October 2018. doi:10.1038/s41582-018-0058-z. PMID 30171200. https://discovery.ucl.ac.uk/id/eprint/10057189/. "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.". 
  4. ↑ "Uman-type neurofilament light antibodies are effective reagents for the imaging of neurodegeneration". Brain Communications 5 (2). 2023-03-02. doi:10.1093/braincomms/fcad067. PMID 37091583. 
  5. ↑ "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 22 (5): 699–706. September 2022. doi:10.17305/bjbms.2021.7326. PMID 35490364. 
  6. ↑ "Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis". PLOS ONE 11 (10). 2016. doi:10.1371/journal.pone.0164625. PMID 27732645. Bibcode: 2016PLoSO..1164625X. "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.". 
  7. ↑ "Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study". Neuropsychiatric Disease and Treatment 14: 2241–2254. 2018. doi:10.2147/NDT.S173280. PMID 30214214. "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.". 
  8. ↑ "Biomarkers for Alzheimer's disease beyond amyloid and tau". Nature Medicine 25 (2): 201–203. February 2019. doi:10.1038/s41591-019-0348-z. PMID 30728536. https://discovery.ucl.ac.uk/id/eprint/10069672/. 
  9. ↑ "Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease". Nature Medicine 25 (2): 277–283. February 2019. doi:10.1038/s41591-018-0304-3. PMID 30664784. 
  10. ↑ "Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease?". PLOS ONE 12 (2). 27 February 2017. doi:10.1371/journal.pone.0172762. PMID 28241046. Bibcode: 2017PLoSO..1272762N. 
  11. ↑ "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 22 (5): 699–706. April 2022. doi:10.17305/bjbms.2021.7326. PMID 35490364. 
  12. ↑ "A neuronal blood marker is associated with mortality in old age". Nature Aging 1 (2): 218–225. February 2021. doi:10.1038/s43587-021-00028-4. PMID 37118632. 
  13. ↑ 13.0 13.1 "Neurofilaments and Neurofilament Proteins in Health and Disease". Cold Spring Harbor Perspectives in Biology 9 (4). April 2017. doi:10.1101/cshperspect.a018309. PMID 28373358. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 "Neurofilaments". Synaptic Systems GmbH. 2025. https://www.sysy.com/neurofilaments?page22=2. 
  15. ↑ 15.0 15.1 15.2 "Neurofilaments at a glance". Journal of Cell Science 125 (Pt 14): 3257–63. July 2012. doi:10.1242/jcs.104729. PMID 22956720. 
  16. ↑ "Uman-type neurofilament light antibodies are effective reagents for the imaging of neurodegeneration". Brain Communications 5 (2). 2023. doi:10.1093/braincomms/fcad067. PMID 37091583. 
  17. ↑ 17.0 17.1 17.2 "Interactions Between Purkinje Cells and Granule Cells Coordinate the Development of Functional Cerebellar Circuits". Neuroscience 462: 4–21. May 2021. doi:10.1016/j.neuroscience.2020.06.010. PMID 32554107. 
  18. ↑ "Interaction domains of neurofilament light chain and brain spectrin". The Biochemical Journal 275 (2): 521–527. April 1991. doi:10.1042/bj2750521. PMID 1902666. 
  19. ↑ "PKN associates and phosphorylates the head-rod domain of neurofilament protein". The Journal of Biological Chemistry 271 (16): 9816–9822. April 1996. doi:10.1074/jbc.271.16.9816. PMID 8621664. 
  20. ↑ "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. doi:10.1074/jbc.M207211200. PMID 12226091. 

Further reading



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