The 2022 Lady Estelle Wolfson lectureship on neurofilaments. Issue 3 (19th September 2022)

• Record Type: Journal Article
• Authors: Petzold, Axel
• Is Part Of: Journal of neurochemistry. Volume 163:Issue 3(2022)
• Page Start: 179
• Page End: 219
• Publication Date: 2022-09-19
• Subjects: biomarker -- diagnosis -- neurofilament -- prognosis -- treatment trial; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15682
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), α ‐internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot–Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post‐translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease. Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33 meta‐analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research. Abstract : Neurofilament proteins (Nf) are a validated bodyfluid biomarker for neurodegeneration. Nf are obligate, heteropolymers of different molecular sizes. Molecular assembly is hierarchical. Mutations and post‐translational modifications are extensive, relevant to pathology and immunotest development. The mature Nf proteins contain intrinsically unstructured polyampholytic regions relevant for protein–protein interactions. Contemporary state‐of‐the art laboratory tests quantify small, stable, soluble, proteolytic Nf breakdown products. Review and meta‐analyses of the clinical spectrum illustrate the relationship with neurodegeneration. Interpretation of increased human body fluid Nf concentration conveys information on the following: (i) diagnosis; (ii) prognosis; (iii) monitoring of progression and (iv) treatment trial endpoints.