The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

• Published in: Molecular neurodegeneration Vol. 15; no. 1; pp. 45 - 16
• Main Authors: Suk, Terry R., Rousseaux, Maxime W. C.
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.08.2020; BioMed Central; BMC
• Subjects: ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Autophagy; Autopsy; Cytoplasm; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA-Binding Proteins - metabolism; Gene expression; Genetic aspects; Humans; Localization; Mislocalization; Molecular weight; Mutation; Nucleocytoplasmic shuttling; Pathogenesis; Pathology; Phosphorylation; Protein binding; Protein interaction; Proteins; Review; Splicing; TDP-43; TDP-43 Proteinopathies - pathology; ALS; Pathology; Mislocalization; Nucleocytoplasmic shuttling; TDP-43
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-020-00397-1

Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gain- and loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclear-to-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain- and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain- and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.