TY - JOUR
T1 - The 2022 Lady Estelle Wolfson lectureship on neurofilaments
AU - Petzold, Axel
N1 - Funding Information: I am grateful to the Royal College of Physicians, London, UK for the generous reward of the 2022 Lady Estelle Wolfson Lectureship. The lecture was given at the Medicine 2022 conference on 01.04.2022. This review was not funded. Figures were re-drawn by Victoria Morus on the basis of a draft provided by the author. The molecular structures were created in Pymol (https://pymol.org/2/). Publisher Copyright: © 2022 The Author. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
PY - 2022/11
Y1 - 2022/11
N2 - 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), (Formula presented.) -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. (Figure presented.).
AB - 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), (Formula presented.) -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. (Figure presented.).
KW - biomarker
KW - diagnosis
KW - neurofilament
KW - prognosis
KW - treatment trial
UR - http://www.scopus.com/inward/record.url?scp=85138315616&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/jnc.15682
DO - https://doi.org/10.1111/jnc.15682
M3 - Review article
C2 - 35950263
SN - 0022-3042
VL - 163
SP - 179
EP - 219
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 3
ER -