Neurofilaments in Neurons

What is Neurofilaments?

Neurons are polarised cells with highly specialized compartments (perikaryon, dendrites, axon). Based on differences in diameter and protein components, the neuron cytoskeleton comprises microtubules, microfilaments, and neurofilaments, which play a crucial role in maintaining structure and function. Neurofilaments make up the central intermediate filament (IF) system in mature neurons. Neurofilament proteins are exclusively expressed in neurons in the central (CNS) and peripheral (PNS) nervous systems. Neurofilaments are obligate heteropolymers and developmentally regulated and reflect neuronal maturation. They are most abundant in axons and required for proper radial growth of axons. Furthermore, abnormal accumulation and assembly of neurofilaments, similar to that commonly found in human motor neuron disease, can directly cause motor neuron dysfunction.

Fig.1 Expression of neurofilament during development of the nervous system. (Laser-Azogui, 2015)

Axonal Transport of Neurofilaments

Neurofilaments are synthesized in the cell body and travel long distances along axons to reach their function sites. After their synthesis, neurofilament proteins are quickly translocated into the axons and assemble into filamentous structures. It is speculated that neurofilament proteins exist in multiple assembly forms during axonal transport and that the transported NF subunits assemble into filaments during the transport. The movement of neurofilaments in axons occurs along microtubule tracks by the retrograde motor dynein and the anterograde motor kinesin-1. Neurofilament proteins are transported in the slow transport component, which carries at varying slow velocities a wide assortment of nonvesicular protein cargoes. Therefore, the current understanding of neurofilament transport is that they are transported bi-directionally in the axon along microtubules through standard motors such as dynein and kinesin. The average slow rate of neurofilament movement is because neurofilament structures spend most of their time (>99%) pausing in the axon.

Fig.2 The neurofilament network in axons. (Yuan, 2017)

Roles of Neurofilaments in Neurons

Neurofilaments are networked with other cytoskeletal elements to organize the cellular environment and position organelles. Neurofilaments have a role in organizing cellular architecture and in positioning axonal mitochondria and endoplasmic reticulum. In addition, neurofilaments are an essential regulator of mitochondrial morphology, dynamics, and motility. Neurofilaments may also bind to other cytoskeletal components through linkers, which mediate interactions with the actin microfilament network.

• Support axonal structure

As a member of the cytoskeletal system, neurofilaments work with other types of neuron cytoskeleton to enhance structural integrity, cell shape, and cell and organelle motility. One recognized function of neurofilaments involves controlling radial growth of large myelinated axons and their conduction velocity. Neurofilaments are particularly abundant in neurons with large diameter axons (>5 mM). Earlier correlative evidence showed a linear relationship between neurofilament number and cross-sectional area throughout average radial growth. During re-growth following axonal injury, observations strongly suggested that neurofilaments are intrinsic determinants of radial growth. Neurofilaments are essential for radial growth and maintenance of axonal caliber and for myelination, which are significant determinants of the speed of action potential conduction. Thus, neurofilaments are essential for the radial growth and structural stability of myelinated axons and achieve the optimal propagation speed of electrical impulses along axons.

Fig.3 Formation of the axonal neurofilament network. (Yuan, 2017)

• Protective effects

The neurofilament network’s mechanical properties provide protection from repetitive mechanical stress that occurs with movement. The viscoelastic properties of neurofilaments are influenced by subunit composition, which plays a pivotal role in increasing stretching properties by lowering resistance. Many studies support a protective effect for the depletion of axonal neurofilaments or the accumulation of neurofilament proteins. Another possible explanation of neurofilament proteins, the protective function may relate to the normal function of these proteins.

• The possible function of KSP repeats

The prominent characteristic of neurofilaments is the multiple KSP repeats in their C-termini. Neurofilaments proteins, especially NF-H, can assimilate stress-related modifications/adducts to balance cellular conditions until they are degraded at the synapse, or the modifications are reversed in the cytoplasm during the lifespan of neurons. This mechanism may work both in physiology and pathology to clearance free radical products and prevent cytoskeletal abnormalities during the neurodegenerative process. KSP repeats are likely to be one of the critical components performing this regulation.

Neurofilaments and Neurodegenerative Diseases

Recent studies have suggested that neurofilaments are closely related to many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, and diabetes. Many changes in the neurofilaments are sufficient to produce most of the pathological changes encountered in neurodegenerative diseases. Many alterations can potentially lead to the accumulation of neurofilament proteins, including dysregulation of neurofilament protein synthesis, defective axonal transport, abnormal phosphorylation, and proteolysis. In addition, neurofilament gene mutations cause several neuroaxonal disorders characterized by disrupted subunit assembly and neurofilament aggregation. Disruption of neurofilament organization and expression or metabolism of neurofilament proteins is characteristic of specific neurological syndromes. Furthermore, abnormal accumulation of neurofilaments has been seen as a common early feature of many motor neuron disorders and sensorimotor neuropathies.

The accumulation of neurofilaments has been known as a general hallmark for several neurodegenerative diseases. A promising and reliable biomarker should say something about the stage of the disease, the prognosis, and the response to treatment. Increased neurofilament level appears to reflect ongoing neuronal damage making it a potentially exciting biomarker. In animal studies, neurofilament levels have been used as a marker of axonal damage for decades. Neurofilament proteins were first used as markers of neuronal damage in a study of patients with ALS and patients with Alzheimer’s disease in humans. The field of neurofilament research is rapidly expanding, and neurofilament levels are under investigation as markers of disease activity and progression in several different neurological conditions, including stroke, ALS, frontotemporal dementia, and multiple sclerosis.

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References

1. Laser-Azogui, A.; et al. Neurofilament assembly and function during neuronal development. Current opinion in cell biology. 2015, 32, 92-101.
2. Yuan, A.; et al. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harbor perspectives in biology. 2017, 9(4), a018309.