# NEFL

## Overview
The NEFL gene encodes the neurofilament light chain protein, a key structural component of the intermediate filaments in neurons. This protein is essential for maintaining the structural integrity and proper function of neurons, particularly in the formation and stability of the neuronal cytoskeleton. Neurofilament light chain, categorized as an intermediate filament protein, plays a critical role in supporting axonal caliber, which is crucial for efficient nerve impulse transmission. Mutations in the NEFL gene are associated with several neurodegenerative conditions, including Charcot-Marie-Tooth disease, highlighting its importance in neural health and disease (Jordanova2003Mutations; Perrot2008Review). The protein's structure includes a central rod domain critical for dimerization and interaction with other neurofilament subunits, which is essential for the assembly of the neurofilament network within axons (Yuan2017Neurofilaments).

## Structure
The NEFL protein, also known as neurofilament light chain, is a crucial component of the neurofilaments in neurons, playing a significant role in the assembly and stability of the neuronal cytoskeleton. The molecular structure of NEFL includes a central alpha-helical rod domain flanked by globular head and tail domains. The central rod domain, approximately 310 amino acids in length, contains hydrophobic heptad repeats crucial for the formation of coiled-coil structures, which facilitate the dimerization with other neurofilament subunits such as NEFM or NFH (Yuan2017Neurofilaments; Perrot2008Review).

NEFL undergoes significant post-translational modifications, which are essential for its function and assembly. These modifications include phosphorylation and O-linked glycosylation. Phosphorylation sites such as Ser-51 and Ser-55 are particularly critical, as they influence the assembly and stability of neurofilaments. The phosphorylation of these sites by protein kinases like PKA and PKC can prevent assembly or cause disassembly when incorporated into filaments (Perrot2008Review).

Additionally, NEFL can form homopolymers both in vitro and in vivo, particularly in humans, unlike in rodents where it forms obligate heteropolymers with other NF subunits (Perrot2008Review). This ability to form various polymeric structures highlights the importance of NEFL in maintaining the structural integrity of neurons.

## Function
The NEFL gene encodes the neurofilament light chain protein, which is a fundamental component of the neurofilament network within neurons. This protein plays a crucial role in maintaining the structural integrity and function of neurons by forming intermediate filaments necessary for maintaining axonal caliber. The proper assembly and functioning of these neurofilaments are essential for supporting the shape and size of neurons, which in turn influences the conduction velocity of nerve impulses across axons (Jordanova2003Mutations; De2001Further).

NEFL is involved in various cellular functions, including the intracellular transport of neurotransmitters to axons and dendrites, which is vital for normal neuronal operations and signaling (Huang2013The; Chen2012Role). The protein consists of a head, rod, and tail domain, with the rod domain segmented into four coil subdomains separated by linker molecules, and the tail domain containing two subdomains, with the B subdomain being acidic (De2001Further).

Mutations in the NEFL gene can lead to neurodegenerative diseases by affecting the stability and function of neurofilaments, as evidenced by various animal models, including knockout mice that exhibit reduced axon caliber and delayed regeneration of myelinated axons (De2001Further).

## Clinical Significance
Mutations in the NEFL gene, which encodes the neurofilament light chain protein, are primarily associated with various forms of Charcot-Marie-Tooth disease (CMT), a group of inherited neurological disorders affecting peripheral nerves. These mutations can manifest in both axonal and demyelinating forms of neuropathy, often leading to symptoms such as muscle weakness and atrophy, sensory loss, and decreased tendon reflexes. The mutations include missense, nonsense, frameshift, and deletion types, affecting different domains of the NEFL protein (Jordanova2003Mutations; Stone2021A).

Clinical manifestations of NEFL-related CMT can vary widely, even among individuals with the same mutation, suggesting a complex interplay of genetic and environmental factors in disease expression. Some patients experience severe, early-onset forms of the disease, including additional symptoms such as hearing loss, tremor, and ataxia (Lerat2019A; Jordanova2003Mutations). Electrophysiological studies in these patients often show reduced nerve conduction velocities, indicative of significant nerve dysfunction (Stone2021A).

Furthermore, NEFL mutations have been implicated in sporadic cases of CMT, where de novo mutations occur, adding complexity to the genetic landscape of the disease (Jordanova2003Mutations). The broad clinical spectrum associated with NEFL mutations does not correlate directly with the mutation's position within the gene, indicating that all domains of the NEFL protein are crucial for its function (Kotaich2023Neurofilaments).

## Interactions
NEFL, the neurofilament light chain protein, engages in several critical interactions that are essential for its function in neurons. NEFL interacts with other neurofilament subunits such as neurofilament medium chain (NEFM) and neurofilament heavy chain (NEFH) to form the core components of neurofilaments, which are crucial for maintaining neuronal structure and function (Gentil2015Neurofilament). These interactions involve the formation of coiled-coil dimers through antiparallel association, which then assemble into long filaments essential for the structural integrity of neurons.

Additionally, NEFL's interaction with stathmin and Stat3 plays a significant role in modulating microtubule dynamics within axons. The interaction between NEFL and stathmin is studied using immunoprecipitation techniques, revealing that NEFL depletion leads to an increased interaction between Stat3 and stathmin. This interaction inhibits the microtubule destabilizing activity of stathmin, thereby preventing axonal degeneration in motoneurons (Yadav2016Neurofilament).

NEFL is also subject to post-translational modifications such as O-GlcNAcylation, which influences its interactions and assembly states. O-GlcNAcylation of NEFL affects its ability to form complexes with other proteins like INA (internexin neuronal intermediate filament protein, alpha), enhancing their interactions and impacting the assembly and function of neurofilaments (Huynh2023O-GlcNAcylation). These glycan-mediated interactions are crucial for the normal assembly and function of neurofilaments, highlighting the importance of NEFL in neuronal structural dynamics.


## References


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