Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

• Published in: Frontiers in molecular neuroscience Vol. 12; p. 25
• Main Authors: Prasad, Archana, Bharathi, Vidhya, Sivalingam, Vishwanath, Girdhar, Amandeep, Patel, Basant K.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 14.02.2019; Frontiers Media S.A
• Subjects: Amyloid; Amyotrophic lateral sclerosis; amyotrophic lateral sclerosis (ALS); Deoxyribonucleic acid; Disaggregation; DNA; Endocytosis; Frontotemporal dementia; frontotemporal lobar degeneration (FTLD); Inclusion bodies; liquid-liquid phase separation (LLPS); Localization; mitotoxicity; Molecular modelling; Motor neuron diseases; Mutation; Nek1 protein; Neurodegeneration; Neuroscience; Oligomerization; Pathology; Post-translation; Protein folding; Protein turnover; Proteins; Ribonucleic acid; RNA; Spinal cord; Superoxide dismutase; TDP-43; Toxicity; ALS therapeutics; mitotoxicity; TDP-43; frontotemporal lobar degeneration (FTLD); liquid-liquid phase separation (LLPS); endocytosis; prion; amyotrophic lateral sclerosis (ALS)
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2019.00025

TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90-95%) are sporadic (sALS), among familial ALS cases 5-10% involve the inheritance of mutations in the gene and the remaining (90-95%) are due to mutations in other genes such as: , and etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like aggregation, its physiological vs. pathological oligomerization , liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.