The 2022 Lady Estelle Wolfson lectureship on neurofilaments

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), -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

Remodeling of the neuromuscular junction in myasthenia gravis increases serum neurofilament heavy chain levels

“…In an experimental setting Nf might prove a valuable biomarker for longitudinal studies of the NMJ 15,19,20 . Consistent with these data and from what has been demonstrated for the use of Nf in other neurological conditions, 9 the value in clinical practice may include improvement of prognostic accuracy and monitoring of treatment response.…”

“…The ROC AUC and diagnostic sensitivity were good. There are no previous data on blood or cerebrospinal fluid levels of either the NfH, Nf medium or NfL chains in patients with MG 9 …”

“…Alternatively, if using NfL instead of NfH, bespoke NfL Z‐scores 16 can be used. Expanding on this, future studies should explore the adaptive Nf isoform stoichiometry in response to progressive and systemic MG 9 …”

“…Yet another limitation, is that the relationship between Nf levels and height, weight, and body mass index is not known and that our cohort was not powered for this assessment. Future research should include these data alongside renal function, blood glucose levels, types of nourishment, physical activity and timing of blood sampling (diurnal variation) all of which have been found to influence blood Nf levels 9 …”

Role of the Intermediate Filament Protein Peripherin in Health and Disease

“…Peripherin is acetylated at Lys 288 and Lys 398 and methylated at Arg 72 and Arg 98 , even though, in this case, the biological functions of these modifications have not yet been investigated [ 50 ].…”