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Cdc48/VCP and Endocytosis Regulate TDP-43 and FUS Toxicity and Turnover
Guangbo Liu1, Aaron Byrd1, Amanda N Warner1
1Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) are aggregation-prone RNA-binding proteins that in ALS can mislocalize to the cytoplasm of affected motor neuron cells, often forming cytoplasmic aggregates in the process. Such mislocalization and aggregation are implicated in ALS pathology, though the mechanism(s) of TDP-43 and FUS cytoplasmic toxicity remains unclear. Recently, we determined that the endocytic function aids the turnover (i.e., protein degradation) of TDP-43 and reduces TDP-43 toxicity. Here, we identified that Cdc48 and Ubx3, a Cdc48 cofactor implicated in endocytic function, regulates the turnover and toxicity of TDP-43 and FUS expressed in Saccharomyces cerevisiae Cdc48 physically interacts and colocalizes with TDP-43, as does VCP, in ALS patient tissue. In yeast, FUS toxicity also depends strongly on endocytic function but not on autophagy under normal conditions. FUS expression also impairs endocytic function, as previously observed with TDP-43. Taken together, our data identify a role for Cdc48/VCP and endocytic function in regulating TDP-43 and FUS toxicity and turnover. Furthermore, endocytic dysfunction may be a common defect affecting the cytoplasmic clearance of ALS aggregation-prone proteins and may represent a novel therapeutic target of promise.
Insights
Cdc48 and endocytic function regulate the turnover and toxicity of TDP-43 and FUS, proteins implicated in Amyotrophic Lateral Sclerosis (ALS). Endocytic dysfunction may be a therapeutic target for clearing these toxic proteins.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease.
- TDP-43 and FUS are aggregation-prone proteins implicated in ALS pathogenesis.
- Mechanisms of TDP-43 and FUS cytoplasmic toxicity are not fully understood.
Purpose of the Study:
- To investigate the role of Cdc48 and its cofactor Ubx3 in regulating TDP-43 and FUS turnover and toxicity.
- To explore the involvement of endocytic function in the clearance of these proteins.
- To identify potential therapeutic targets for ALS.
Main Methods:
- Utilized *Saccharomyces cerevisiae* (yeast) as a model system.
- Assessed the regulation of TDP-43 and FUS turnover and toxicity by Cdc48 and Ubx3.
- Examined protein-protein interactions and cellular localization in yeast and ALS patient tissue.
- Investigated the impact of FUS expression on endocytic function.
Main Results:
- Cdc48 and Ubx3 regulate TDP-43 and FUS turnover and toxicity in yeast.
- Cdc48 physically interacts with and colocalizes with TDP-43 in ALS patient tissue, as does VCP.
- FUS toxicity in yeast depends on endocytic function but not autophagy.
- FUS expression impairs endocytic function, similar to TDP-43.
Conclusions:
- Cdc48/VCP and endocytic function play a critical role in regulating TDP-43 and FUS toxicity and turnover.
- Endocytic dysfunction may be a common defect in ALS, affecting the clearance of aggregation-prone proteins.
- Targeting endocytic pathways could offer a novel therapeutic strategy for ALS.
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