Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 26, Issue 6, Pages 575-592Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14728222.2022.2083958
Keywords
Aggregation; ALS; mislocalization; neurodegeneration; proteinopathy; TDP-43; therapeutics
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ALS is a fatal neurodegenerative disease without effective treatment. TDP-43, a major therapeutic target in ALS, has been studied for its cellular functions and pathological effects. Various pathways have been explored for mitigating TDP-43 pathology in ALS.
Introduction Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that lacks an effective treatment. Aggregates of the TAR DNA-binding protein-43 (TDP-43) are observed in 97% of all ALS cases, thus making this protein a major therapeutic target in ALS. Areas covered The authors describe the major cellular functions of TDP-43 and the features and consequences of TDP-43 proteinopathy. Drawing from fundamental and preclinical studies on cellular and animal TDP-43 models of ALS and selected clinical trials, the major pathways that have been targeted for the mitigation of TDP-43 pathology in ALS are discussed. The authors provide insights on the approaches targeting the tendency of TDP-43 for aggregation, defective nucleocytoplasmic transport, dysfunctional proteostasis, abnormal stress granule dynamics, and pathological post-translational modifications of TDP-43. Expert opinion The complexity of ALS and TDP-43 proteinopathy generates challenges for the development of novel therapeutic approaches. However, the critical involvement of TDP-43 in the initiation and progression of ALS, makes it a promising therapeutic target. Further research should be centered on the development of precision strategies, consideration of patient subgroups, the prevention of the mislocalization of TDP-43 and restoration of the lost functions of TPD-43.
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