Shortened TDP-43 isoforms form steric zippers driving aggregation and mislocalization in ALS pathology
By
James Shorter
Summary
This scientific research article investigates shortened TDP-43 (sTDP-43) splice isoforms and their role in neurodegenerative disorders like ALS. Despite lacking most of the prion-like domain (PrLD), sTDP-43 exhibits pronounced insolubility and aggregation. The study reveals that sTDP-43 isoforms form isoform-specific steric zippers—a type of amyloid-like structure—that drive aberrant assembly and mislocalization of the protein, contributing to ALS pathophysiology. The research provides mechanistic insights into how these shortened isoforms aggregate differently from full-length TDP-43 and are enriched in motor neurons, linking their behavior to disease mechanisms.
Source
Twitter / XShortened TDP-43 isoforms form steric zippers driving aggregation and mislocalization in ALS pathologyscience.orgKey quotes
· 3 pulledPrion-like domain (PrLD)–mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS).
Shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons.
Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility
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