NEFL — Neurofilament Light Chain

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NEFL — Neurofilament Light Chain

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NEFL — neurofilament Light Chain</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>NEFL</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Neurofilament Light Polypeptide (NF-L, NF68)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>8p21.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4747" target="_blank">4747</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000277586" target="_blank">ENSG00000277586</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/162280" target="_blank">162280</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P07196" target="_blank">P07196</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[CMT1F/CMT2E](/diseases/charcot-marie-tooth-disease), [ALS](/diseases/als), [AD](/diseases/alzheimers), [PD](/diseases/parkinsons-disease) (biomarker </td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Motor Neurons](/cell-types/motor-neurons), Cortical Neurons, Peripheral Nerves, All Neurons (ubiquitous)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/a

...

NEFL — Neurofilament Light Chain

NEFL (Neurofilament Light Chain)

Introduction

Nefl — [Neurofilament Light](/biomarkers/neurofilament-light-chain-nfl) Chain is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Mermaid diagram (expand to render)

NEFL ([neurofilament-light](/biomarkers/neurofilament-light-chain-nfl) Polypeptide, also known as NF-L or NF68) is a gene on chromosome 8p21.2 encoding the light chain subunit of neurofilaments, the major intermediate filaments of [neurons](/entities/neurons). Neurofilament light chain is the obligate core subunit of all neurofilament heteropolymers and is essential for proper neurofilament assembly, axonal [^5] caliber maintenance, and nerve conduction velocity ([Lee & Cleveland, 1996](https://doi.org/10.1146/annurev.ne.19.030196.001155)). The NEFL gene product forms heterodimers with neurofilament medium chain (NEFM) and neurofilament heavy chain (NEFH), and can also incorporate alpha-internexin (INA) or peripherin (PRPH) as fourth subunits.

NEFL is of dual significance in neurodegenerative disease: mutations in NEFL cause [charcot-marie-tooth-disease](/diseases/charcot-marie-tooth-disease) types 1F and 2E (CMT1F/CMT2E), while the NEFL gene product — [nfl-protein](/proteins/nfl-protein) — has emerged as the most important fluid biomarker of neuronal injury and neurodegeneration across virtually all neurological conditions, including [alzheimers](/diseases/alzheimers-disease), [als](/diseases/als), [parkinsons](/diseases/parkinsons-disease), and [multiple-sclerosis](/diseases/multiple-sclerosis) ([Khalil et al., 2018](https://doi.org/10.1038/s41582-018-0058-z)).

Function

Neurofilament Structure and Assembly

The NEFL protein is a 543-amino-acid polypeptide (~62 kDa) composed of three structural domains characteristic of intermediate filament proteins:

Head domain (N-terminal): contains phosphorylation sites that regulate filament assembly and disassembly
Rod domain (central): alpha-helical coiled-coil domain responsible for dimerization and filament polymerization
Tail domain (C-terminal): shorter than NEFM and NEFH tails; projects from the filament surface

Neurofilament assembly begins with NEFL forming obligate heterodimers with NEFM or NEFH through their rod domains. These dimers associate in an antiparallel, staggered manner to form tetramers, which then laterally associate into protofilaments and mature 10-nm intermediate filaments. NEFL is unique among neurofilament subunits in that it can self-assemble into homopolymers in vitro, though in vivo it always forms heteropolymers.

Axonal Caliber Determination

Neurofilaments are the primary determinant of axonal caliber in myelinated [neurons](/entities/neurons). Axonal diameter directly determines nerve conduction velocity, as larger axons have lower resistance to electrical signal propagation. The density and spacing of neurofilaments — regulated by the phosphorylation state of NEFM and NEFH tail domains — control axon diameter. Loss of NEFL dramatically reduces neurofilament content and results in thinner axons with reduced conduction velocity, even in the absence of overt neurodegeneration ([Zhu et al., 1997](https://doi.org/10.1083/jcb.138.6.1307)).

Axonal Transport

Neurofilaments undergo slow axonal transport (Component a, ~0.1-1 mm/day) from the cell body to the distal axon. NEFL-containing neurofilaments move in a "stop-and-go" pattern along microtubule tracks, with long pauses interspersed with brief movements. This transport is mediated by kinesin (anterograde) and [dynein](/mechanisms/dynein) (retrograde) motors. Impaired neurofilament transport leads to perikaryal accumulation of neurofilaments, a pathological hallmark of several neurodegenerative diseases.

Neuronal Cytoskeletal Integrity

Beyond structural support, neurofilaments serve as scaffolds for organelles, mitochondria, and signaling molecules within the axon. They interact with microtubules and actin filaments to maintain the axonal cytoskeleton. NEFL also has roles in synaptic function, as neurofilaments are present in synaptic terminals where they may regulate neurotransmitter release through interactions with synaptic vesicle-associated proteins.

Disease Associations

Charcot-Marie-Tooth Disease (CMT1F/CMT2E)

Mutations in NEFL cause autosomal dominant [charcot-marie-tooth-disease](/diseases/charcot-marie-tooth-disease), classified as CMT1F (demyelinating) or CMT2E (axonal) depending on nerve conduction velocities. Over 20 pathogenic mutations have been identified, including:

Missense mutations (dominant): cluster in the rod domain (coiled-coil region) and head domain; disrupt neurofilament assembly, causing dominant-negative aggregation of neurofilaments in perikarya. Patients typically present with early-onset severe neuropathy with foot deformity, distal muscle weakness and atrophy, and moderately to severely reduced nerve conduction velocities ([Mersiyanova et al., 2000](https://pubmed.ncbi.nlm.nih.gov/11220745/); [De Jonghe et al., 2001](https://pubmed.ncbi.nlm.nih.gov/12566280/)).
Nonsense mutations (recessive): cause complete loss of NEFL protein; the recessive phenotype suggests that heterozygous carriers produce sufficient neurofilament from the wild-type allele, while homozygous loss leads to neuropathy through reduced axonal caliber ([Yum et al., 2009](https://pubmed.ncbi.nlm.nih.gov/19158810/)).

iPSC-derived motor [neurons](/entities/neurons) from patients with NEFL mutations show absence of neurofilament light chain protein, disorganized neurofilament networks, and impaired neurite outgrowth ([Sainio et al., 2018](https://pubmed.ncbi.nlm.nih.gov/29868927/)).

Neurofilament Light as a Biomarker (NfL)

The release of NEFL protein ([neurofilament-light](/biomarkers/neurofilament-light-chain-nfl) into cerebrospinal fluid (CSF) and blood [^4] upon axonal damage has made it the preeminent fluid biomarker for neurodegeneration. [neurofilament-light](/biomarkers/neurofilament-light-chain-nfl) levels are elevated in:

[als](/diseases/als) — among the highest [neurofilament-light](/biomarkers/neurofilament-light-chain-nfl) elevations of any disease; strongly prognostic; aids in distinguishing ALS from mimics
[alzheimers](/diseases/alzheimers-disease) — elevated in prodromal and clinical stages; correlates with rate of cognitive decline and brain atrophy
[parkinsons](/diseases/parkinsons-disease) — mildly elevated; helps distinguish PD from atypical parkinsonisms (MSA, PSP, CBD) where [neurofilament-light](/biomarkers/neurofilament-light-chain-nfl) is much higher
[multiple-sclerosis](/diseases/multiple-sclerosis) — reflects acute axonal injury during relapses; used to monitor treatment response
[huntington-pathway](/mechanisms/huntington-pathway) — elevated years before clinical onset; tracks disease progression
[ftd](/diseases/ftd) — elevated; particularly useful for prognosis
Traumatic brain injury — acute elevation proportional to injury severity

The development of ultrasensitive single-molecule array (Simoa) immunoassays enabled measurement of NfL in blood (serum/plasma), making it accessible as a routine clinical biomarker without the need for lumbar puncture ([Khalil et al., 2018](https://doi.org/10.1038/s41582-018-0058-z)).

Other Neurodegenerative Associations

NEFL expression is dysregulated in multiple neurodegenerative conditions beyond those caused by direct NEFL mutations:

In [als](/diseases/als), NEFL mRNA is downregulated in surviving motor [neurons](/entities/neurons), potentially reducing neurofilament production and contributing to axonal atrophy
Perikaryal neurofilament accumulations are a pathological feature of ALS motor neurons, suggesting impaired neurofilament transport
In [alzheimers](/diseases/alzheimers-disease), neurofilament-containing dystrophic neurites surround amyloid plaques

Expression

NEFL is ubiquitously expressed in neurons throughout the central and peripheral nervous systems:

[motor-neurons](/cell-types/motor-neurons) — very high expression; large-caliber myelinated axons require abundant neurofilaments
Peripheral sensory neurons — high expression in dorsal root ganglia neurons
Cortical neurons — expressed across all cortical layers, particularly in large pyramidal neurons
[hippocampal-neurons](/cell-types/hippocampal-neurons) — moderate to high expression
[purkinje-cells](/cell-types/purkinje-cells) — expressed in cerebellar Purkinje neurons
[substantia-nigra](/brain-regions/substantia-nigra) — expressed in [dopaminergic-neurons](/dopaminergic-neurons)

Expression is absent from non-neuronal cells ([astrocytes](/cell-types/astrocytes), [oligodendrocytes](/cell-types/oligodendrocytes), [microglia](/entities/microglia). Neuronal intermediate filaments. Annual Review of Neuroscience, 19:187-217. [DOI](https://doi.org/10.1146/annurev.ne.19.030196.001155)

[Khalil M, Teunissen CE, Otto M, et al. (2018). Neurofilaments as biomarkers in neurological disorders. Nature Reviews Neurology, 14(10):577-589. [DOI](https://doi.org/10.1038/s41582-018-0058-z)

[De Jonghe P, Mersiyanova IV, Nelis E, et al. (2001). Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth Disease type 2E. Annals of Neurology, 49(2):245-249. PMID: 11220745(https://pubmed.ncbi.nlm.nih.gov/11220745/)

[Mersiyanova IV, Perepelov AV, Polyakov AV, et al. (2000). Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth Disease. Brain, 126(Pt 3):590-597. PMID: 12566280(https://pubmed.ncbi.nlm.nih.gov/12566280/)

[Yum SW, Zhang J, Mo K, Li J. (2009). Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth Disease: nonsense mutation probably causes a recessive phenotype. Journal of Human Genetics, 54:94-98. PMID: 19158810(https://pubmed.ncbi.nlm.nih.gov/19158810/)

[Sainio MT, Ylikallio E, Maenpaa L, et al. (2018). Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy. Neurology Genetics, 4(3):e244. [DOI](https://doi.org/10.1212/NXG.0000000000000244)

[Zhu Q, Bhatt DK, et al. (1997). Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Journal of Cell Biology, 138(6):1307-1315. [DOI](https://doi.org/10.1083/jcb.138.6.1307)

[Verde F, Otto M, Silani V. (2021). Neurofilament light chain as biomarker for amyotrophic lateral sclerosis and Frontotemporal Dementia. Frontiers in Neuroscience, 15:679199. [DOI](https://doi.org/10.3389/fnins.2021.679199)

[Yuan A, et al. (2023). Neurofilaments in health and Charcot-Marie-Tooth Disease. Frontiers in Cell and Developmental Biology, 11:1275155. [DOI](https://doi.org/10.3389/fcell.2023.1275155)

[Gaetani L, Blennow K, et al. (2019). Neurofilament light chain as a biomarker in neurological disorders. Journal of Neurology, Neurosurgery and Psychiatry, 90(8):870-881. [DOI](https://doi.org/10.1136/jnnp-2018-320106)

Brain Atlas Resources

[Allen Brain Atlas](https://brain-map.org)
[Allen Human Brain Atlas: NEFL search](https://human.brain-map.org/microarray/search/show?search_term=NEFL)
[Allen Mouse Brain Atlas: NEFL search](https://mouse.brain-map.org/search/index.html?query=NEFL)
[Allen Cell Type Atlas](https://portal.brain-map.org/atlases-and-data/rnaseq)
[BrainSpan Developmental Transcriptome](https://www.brainspan.org)

External Links

[NCBI Gene: NEFL](https://www.ncbi.nlm.nih.gov/gene/4747)
[OMIM: 162280](https://www.omim.org/entry/162280)
[UniProt: P07196](https://www.uniprot.org/uniprot/P07196)
[Ensembl: ENSG00000277586](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000277586)
[GeneCards: NEFL](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NEFL)
[Allen Brain Atlas: NEFL](https://human.brain-map.org/microarray/search/show?search_term=NEFL)

Background

The study of Nefl — Neurofilament Light Chain has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

Unknown, <references> (n.d.)

Pathway Diagram

The following diagram shows the key molecular relationships involving NEFL — Neurofilament Light Chain discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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NEFL — Neurofilament Light Chain

NEFL — Neurofilament Light Chain

NEFL — Neurofilament Light Chain

NEFL (Neurofilament Light Chain)

Introduction

Overview

Function

Neurofilament Structure and Assembly

Axonal Caliber Determination

Axonal Transport

Neuronal Cytoskeletal Integrity

Disease Associations

Charcot-Marie-Tooth Disease (CMT1F/CMT2E)

Neurofilament Light as a Biomarker (NfL)

Other Neurodegenerative Associations

Expression

Brain Atlas Resources

See Also

External Links

Background

References

Pathway Diagram