NEFH — Neurofilament Heavy Chain
Introduction
Nefh — Neurofilament Heavy 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
flowchart TD
NEFH["NEFH"] -->|"involved in"| NEURODEGENERATIVE_DISEASES["NEURODEGENERATIVE DISEASES"]
NEFH["NEFH"] -->|"involved in"| Amyotrophic_Lateral_Sclerosis["Amyotrophic Lateral Sclerosis"]
NEFH["NEFH"] -->|"involved in"| Cerebral_Ischemia["Cerebral Ischemia"]
NEFH["NEFH"] -->|"associated with"| Neurodegeneration["Neurodegeneration"]
NEFH["NEFH"] -->|"associated with"| Alzheimer["Alzheimer"]
NEFH["NEFH"] -->|"associated with"| Aging["Aging"]
NEFH["NEFH"] -->|"associated with"| Inflammation["Inflammation"]
NEFH["NEFH"] -->|"associated with"| Parkinson["Parkinson"]
NEFH["NEFH"] -->|"associated with"| Senescence["Senescence"]
NEFH["NEFH"] -->|"associated with"| Ms["Ms"]
NEFH["NEFH"] -->|"associated with"| Als["Als"]
NEFH["NEFH"] -->|"phosphorylates"| Senescence["Senescence"]
NEFH["NEFH"] -->|"phosphorylates"| Aging["Aging"]
NEFH["NEFH"] -->|"phosphorylates"| Neurodegeneration["Neurodegeneration"]
style NEFH fill:#4fc3f7,stroke:#333,color:#000
...NEFH — Neurofilament Heavy Chain
Introduction
Nefh — Neurofilament Heavy 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)
NEFH (Neurofilament Heavy Chain) is a gene encoding the heavy subunit of the neuronal intermediate filament protein family. Neurofilaments are essential for maintaining axonal caliber and nerve conduction velocity. The NEFH gene is located on chromosome 22q12.1 and mutations cause Charcot-Marie-Tooth disease type 2 (CMT2) and are implicated in amyotrophic lateral sclerosis (ALS). [@lee1996]
<table class="infobox infobox-gene"> [@xu1998]
<tr> [@lobsiger2002]
<th class="infobox-header" colspan="2">NEFH — Neurofilament Heavy Chain</th> [@perrot2009]
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>NEFH</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Neurofilament Heavy Chain</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>22q12.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4744" target="_blank">4744</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100133" target="_blank">ENSG00000100133</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/162400" target="_blank">162400</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P06744" target="_blank">P06744</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Charcot-Marie-Tooth Disease Type 2](/diseases/cmt)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Large motor neurons, sensory neurons, brain (cortex, hippocampus, cerebellum)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">E800K, S84F, R1652W, Q333X, 8008insC (polyglutamine expansion)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">38 edges</a></td>
</tr>
</table>
Function
Neurofilament Heavy Chain (NF-H) is the largest neurofilament subunit (approximately 200 kDa) and plays critical roles in neuronal biology:
- Axonal caliber maintenance: NF-H, together with NF-L (light) and NF-M (medium) subunits, forms intermediate filaments that determine axonal diameter
- Fast axonal transport: Neurofilaments are transported along microtubules via kinesin and dynein motors
- Synaptic function: Neurofilament accumulation at nodes of Ranvier ensures proper saltatory conduction
- Neuroprotection: NF-H can act as a molecular buffer for calcium and other signaling molecules
Structural Features
NEFH contains several distinctive features:
Head domain: Non-alpha-helical region involved in filament assembly regulation
Rod domain: Alpha-helical coiled-coil responsible for dimerization
Tail domain: Long C-terminal domain with multiple Lys-Ser-Pro (KSP) phosphorylation sites that project outward from the filament coreDisease Associations
Amyotrophic Lateral Sclerosis (ALS)
While NEFH mutations are not a common cause of ALS, they contribute to disease susceptibility and pathogenesis:
- Mutations: Rare pathogenic variants (e.g., E800K) have been identified in ALS patients
- Biomarker: [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) in CSF and blood are major diagnostic and prognostic biomarkers for ALS
- Pathogenesis: Disrupted neurofilament transport leads to axonal dysfunction and motor neuron death
Charcot-Marie-Tooth Disease Type 2 (CMT2)
NEFH mutations cause an axonal (non-demyelinating) form of CMT:
- Phenotype: Motor and sensory neuropathy with onset in adolescence or adulthood
- Features: Distal muscle weakness and atrophy, decreased reflexes, sensory loss
- Inheritance: Autosomal dominant
Other Neurodegenerative Diseases
Neurofilament proteins are affected in several other conditions:
- Chronic traumatic encephalopathy (CTE): Neurofilament accumulation in axons
- Alzheimer's disease: NF-H in neurofibrillary tangles
- Parkinson's disease: Altered neurofilament phosphorylation
- Multiple sclerosis: Neurofilament release as biomarker for axonal injury
Expression
NEFH expression is neuron-specific:
- Motor [neurons](/entities/neurons): Highest expression in large alpha motor neurons of spinal cord
- Sensory neurons: Dorsal root ganglion neurons
- Brain: [Cortex](/brain-regions/cortex) (layer 5 pyramidal neurons), [hippocampus](/brain-regions/hippocampus) (CA1 neurons), cerebellum (Purkinje cells)
- Expression pattern: Neuron-specific, not expressed in glia
Key Publications
Julius N, et al. "Neurofilament heavy chain mutations cause Charcot-Marie-Tooth disease type 2." Brain 2012. [DOI:10.1093/brain/aws222](https://doi.org/10.1093/brain/aws222)
Petzold A. "Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and disease." Brain 2005. [DOI:10.1093/brain/awh269](https://doi.org/10.1093/brain/awh269)
Lu CH, et al. "Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis." Neurology 2012. [DOI:10.1212/WNL.0b013e31825dceeb](https://doi.org/10.1212/WNL.0b013e31825dceeb)Clinical Relevance
Diagnostic Biomarkers
Neurofilament light chain ([NfL](/proteins/nfl-protein) and phosphorylated neurofilament heavy chain (pNfH) are FDA-recognized biomarkers:
- [NfL](/proteins/nfl-protein): Elevated in CSF and plasma in ALS, MS, and other neurodegenerative conditions
- pNfH: Specific marker for axonal injury, used for ALS diagnosis and monitoring
- Timing: Levels increase with disease progression
Therapeutic Strategies
- Gene therapy: AAV-delivered NEFH to restore neurofilament assembly
- Small molecules: Drugs to stabilize neurofilament transport
- Biomarker development: NfL and pNfH for clinical trials and patient stratification
See Also
- [Amyotrophic Lateral Sclerosis](/diseases/als)
- [Charcot-Marie-Tooth Disease](/cell-types/schwann-cells-cmt)
- [Motor Neuron Diseases](/diseases/motor-neuron-disease)
- [Biomarkers](/biomarkers)
- [Axonal Transport](/mechanisms/axonal-transport)
- [Intermediate Filaments](/entities/intermediate-filaments)
External Links
- [NCBI Gene: NEFH](https://www.ncbi.nlm.nih.gov/gene/4744)
- [UniProt: P06744](https://www.uniprot.org/uniprot/P06744)
- [Ensembl: NEFH](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100133)
- [OMIM: 162400](https://omim.org/entry/162400)
Background
The study of Nefh — Neurofilament Heavy 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.
Brain Atlas Resources
NEFH (Neurofilament Heavy Chain) expression and function can be explored through the following Allen Brain Atlas resources:
- [Allen Human Brain Atlas - NEFH](https://human.brain-map.org/microarray/search/show?search_term=NEFH) — Gene expression data across brain regions
- [Allen Cell Type Atlas](https://celltypes.brain-map.org/) — Cell type-specific expression patterns
- [BrainSpan Atlas of the Developing Human Brain](https://www.brainspan.org/) — Developmental expression profiles
- [Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — Mouse brain expression data for comparative studies
See Also
- [Genes Index](/genes)
- [Neurofilament Proteins](/content/proteins)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Julien JP, Mushynski WE, Neurofilaments in health and disease (1998)](https://doi.org/10.1016/s0079-6603(08))
[Lee MK, Cleveland DW, Neuronal intermediate filaments: new progress on functions (1996)](https://doi.org/10.1146/annurev.neuro.19.1.187))
[Xu Z, Marszalek JR, Lee MK, et al, Subtle structural change in the NF-H tail domain caused by phosphorylation produces changes in its aggregation properties (1998)](https://doi.org/10.1074/jbc.273.42.27126))
[Lobsiger CS, Cleveland DW, Neurofilament phosphorylation and axonal degeneration: new insights into the complexity of region-specific pathology (2002)](https://doi.org/10.1038/nrn933))
[Perrot R, Eyer J, Neurofilament polymer integrity during axonal transport (2009)](https://doi.org/10.1111/j.1471-4159.2009.06280.x))Pathway Diagram
The following diagram shows the key molecular relationships involving NEFH — Neurofilament Heavy Chain discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)