Molecular mechanisms of neurofilament alterations and its application in assessing neurodegenerative disorders

Neurofilaments are intermediate filaments present in neurons. These provide structural support and maintain the size and shape of the neurons. Dysregulation, mutation, and aggregation of neurofilaments raise the levels of these proteins in the blood and cerebrospinal fluid (CSF), which are characteristic features of axonal damage and certain rare neurological diseases, such as Giant Axonal Neuropathy and Charcot-Mare-Tooth disease. Understanding the structure, dynamics, and function of neurofilaments has been greatly enhanced by a diverse range of biochemical and preclinical investigations conducted over more than four decades. Recently, there has been a resurgence of interest in post-translational modifications of neurofilaments, such as phosphorylation, aggregation, mutation, oxidation, etc. Over the past twenty years, several rare disorders have been studied from structural alterations of neurofilaments. These disorders are monitored by fluid biomarkers such as neurofilament light chains. Currently, there are many tools, such as Enzyme-Linked Immunosorbent Assay, Electrochemiluminescence Assay, Single-Molecule Array, Western/immunoblotting, etc., in use to assess the neurofilament proteins in Blood and CSF. However, all these techniques utilize expensive, non-specific, or antibody-based methods, which make them unsuitable for routine screening of neurodegenerative disorders. This provides room to search for newer sensitive, cost-effective, point-of-care tools for rapid screening of the disease. For a long time, the molecular mechanisms of neurofilaments have been poorly understood due to insufficient research attempts, and a deeper understanding of them remains elusive. Therefore, this review aims to highlight the available literature on molecular mechanisms of neurofilaments and the function of neurofilaments in axonal transport, axonal conduction, axonal growth, and neurofilament aggregation, respectively. Further, this review discusses the role of neurofilaments as potential biomarkers for the identification of several neurodegenerative diseases in clinical laboratory practice. Graphical abstract of the review (Created using BioRender.com ). • Hyperphosphorylation plays a vital role in neurotoxicity and induces neurofilament aggregation. • Ageing is the most significant factor causing Neurodegenerative disorders. • Single Molecule Array is an ultrasensitive tool that measures fluid biomarkers accurately. • The neurofilament light chain is a potential clinical biomarker for assessing Neurodegenerative disorders.