| NEFL [1] — neurofilament [2] Light Chain | |
|---|---|
| Symbol | NEFL |
| Full Name | Neurofilament Light Polypeptide (NF-L, NF68) |
| Chromosome | 8p21.2 |
| NCBI Gene | 4747 |
| Ensembl | ENSG00000277586 |
| OMIM | 162280 |
| UniProt | P07196 |
| Diseases | CMT1F/CMT2E, ALS, AD, PD (biomarker |
| Expression | Motor Neurons, Cortical Neurons, Peripheral Nerves, All Neurons (ubiquitous) |
Nefl — Neurofilament Light 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.
NEFL ([neurofilament light[/entities/neurofilament-light 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). 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 — [neurofilament light chain (NfL)[/proteins/nfl-protein — has emerged as the most important fluid biomarker of neuronal injury and neurodegeneration across virtually all neurological conditions, including [Alzheimer's disease[/diseases/alzheimers, [ALS[/diseases/als, [Parkinson's disease[/diseases/parkinsons, and [multiple sclerosis[/diseases/multiple-sclerosis (Khalil et al., 2018).
The NEFL protein is a 543-amino-acid polypeptide (~62 kDa) composed of three structural domains characteristic of intermediate filament proteins:
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.
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).
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.
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.
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:
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).
The release of NEFL protein ([NfL[/entities/neurofilament-light into cerebrospinal fluid (CSF) and blood [4] upon axonal damage has made it the preeminent fluid biomarker for neurodegeneration. [NfL[/entities/neurofilament-light levels are elevated in:
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).
NEFL expression is dysregulated in multiple neurodegenerative conditions beyond those caused by direct NEFL mutations:
NEFL is ubiquitously expressed in neurons throughout the central and peripheral nervous systems:
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
2. [Khalil M, Teunissen CE, Otto M, et al. (2018). Neurofilaments as biomarkers in neurological disorders. Nature Reviews Neurology, 14(10):577-589. DOI
3. [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/)
4. [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/)
5. [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/)
6. [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
7. [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
8. [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
9. [Yuan A, et al. (2023). Neurofilaments in health and Charcot-Marie-Tooth Disease. Frontiers in Cell and Developmental Biology, 11:1275155. DOI
10. [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
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.