The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Abstract

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.

Keywords: ALS; Mislocalization; Nucleocytoplasmic shuttling; Pathology; TDP-43.

Fig. 1

Structure of TDP-43 including functional domains and identified short-species. M1,M3,M5 (Red): Mitochondria Localization Sequences; NLS (Turquoise): Bipartite Nuclear Localization Sequence; RRM1,RRM2 (Blue): RNA Recognition Motif; NES (Light Purple): Controversial Nuclear Export Signal; NES (Dark Purple): Nuclear Export Signal; CTD (Grey): C-Terminal Domain; Yellow Box: Alternate Amino Acid Sequence (N-Terminus of “Isoform 2” and C-Terminus of “Short TDP-43”); Dashed Lines: Cleavage Sites

Fig. 2

TDP-43 (Red) mislocalizes (partially or completely) from the nucleus to the cytoplasm due to genetic and/or environmental factors causing deleterious effects to the cell. Prolonged mislocalization promotes aggregation. Under physiological conditions the cell can clear small TDP-43 aggregates through proteasomal, endosomal, or autophagic degradation. Prolonged The accumulation of TDP-43 aggregates disrupts physiological functioning (e.g. sequestration of SQSTM1) thereby exacerbating pathology and promoting neuronal degeneration. Early interventions normalizing TDP-43 localization hold the potential to prevent cellular demise