Department of Neurodegeneration, Queen Square Insitute of Neurology, UCL, London, UK.
J Neurochem. 2022 Nov;163(3):179-219. doi: 10.1111/jnc.15682. Epub 2022 Sep 19.
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 meta-analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research.
神经丝蛋白（Nf）已被验证并确立为神经退行性病变的可靠体液生物标志物。本综述涵盖了七种 Nf 同工型，即神经丝轻链（NfL）、两种神经丝中间丝（NfM）的剪接变体、两种神经丝重链（NfH）的剪接变体、-中间丝（INA）和外周蛋白（PRPH）。讨论了 Nf 的遗传和表观遗传方面，因为它们与神经退行性疾病和肿瘤学有关。涵盖了所有 Nf 同工型的突变的综合列表包括肌萎缩侧索硬化症、Charcot-Marie-Tooth 病、脊髓性肌萎缩症、帕金森病和路易体痴呆症。其次，重点介绍了 Nf 氨基酸残基的翻译后修饰（PTM）的扩展领域。与引起神经退行性病变和人类自身免疫的 PTM 一起，审查了蛋白质结构方面。NF PTM、组装和化学计量的分子可视化利用了 Alphafold2 建模。讨论了 Nf 在细胞水平和轴突运输上的功能意义。神经丝聚集体形成和蛋白水解降解被认为与生物标志物测试和疾病有关。同样，考虑了 Nf 在体外实验中的化学计量以及在神经退行性变中的补偿机制。对来自医学各个领域的 87 种疾病的 Nf 进行综述，随后对 33 项关于 Nf 体液水平的荟萃分析进行了批判性评估。综述最后考虑了临床试验设计，并对未来的研究进行了展望。
