Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19
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View abstract on PubMed
Summary
This summary is machine-generated.The study reveals that USP19 protein promotes the secretion of misfolded TDP-43, a key factor in amyotrophic lateral sclerosis (ALS). This discovery offers potential new therapeutic targets for ALS and related proteinopathies.
Area Of Science
- Cell Biology
- Neuroscience
- Molecular Biology
Background
- Proteinopathies like ALS involve misfolded protein accumulation.
- Cellular quality control systems often fail to clear these aberrant proteins.
- Misfolded TDP-43 aggregates are a hallmark of ALS pathology.
Purpose Of The Study
- To investigate the role of Endoplasmic Reticulum-associated ubiquitin peptidase USP19 in the secretion of misfolded TDP-43.
- To elucidate the cellular and molecular mechanisms underlying USP19-mediated secretion of misfolded proteins.
Main Methods
- Overexpression of USP19 in cellular models.
- Analysis of protein secretion using soluble and aggregated TDP-43.
- Investigation of cellular compartments (autophagosomes, endosomes, lysosomes).
- Utilizing dominant-negative mutants and small interfering RNAs (siRNAs).
Main Results
- USP19 overexpression significantly enhances the secretion of both soluble and aggregated misfolded TDP-43.
- USP19's ER anchoring and ubiquitin peptidase activity are essential for this secretion.
- The process involves early autophagosomal and late endosomal/amphisomal compartments, but not lysosomes.
- Key cellular trafficking factors (ATG7, ESCRT-O, Rab GTPases, VAMP7) and cochaperone DNAJC5/CSPα modulate USP19-mediated secretion.
Conclusions
- USP19 plays a critical role in the novel misfolding-associated protein secretion (MAPS) pathway for TDP-43.
- This mechanism highlights cellular strategies for managing misfolded protein export.
- Findings suggest potential therapeutic avenues for ALS and other proteinopathies targeting USP19.
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