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Dec 11

Research Bit: Mechanistic and therapeutic insights into repeat expansion disorders

Research Bits
The Packard Center welcomed members from Len Petrucelli's lab at the Mayo Clinic to a recent Investigator's meeting.

Meeting Date: December 11, 2020

Presenter: Yongjie Zhang (from the Len Petrucelli Lab)

Talk Title: Mechanistic and therapeutic insights into repeat expansion disorders


What was the question being asked?

The cytoplasmic mislocalization and aggregation of the protein TDP-43 is a pathologic hallmark of ALS and related neurodegenerative diseases. Drs. Zhang and Petrucelli are working to understand how dipeptide repeat proteins (DPRs) made as a result of the C9orf72 repeat expansion contribute to the aggregation of TDP-43. Previous work in the Petrucelli lab has shown that of the five DPRs that can be made from the C9orf72 repeat expansion, Poly-GR is most closely associated with TDP-43 aggregates. As a result, their current work aims to understand the relationship between Poly-GR and TDP-43 aggregation.

Why is this important for ALS research?

TDP-43 pathology is observed in ~97% of ALS cases and ~50% of FTD cases. However, little is known regarding how TDP-43 mislocalizes and aggregates in the cytoplasm during disease. Further, it is unknown how these aggregates may contribute to disease pathogenesis. Thus, understanding the mechanisms by which TDP-43 aggregation occurs is essential for identifying new biological processes or specific protein targets that may be amenable to therapeutic intervention.

What was the take-home message?

Drs. Zhang and Petricuelli found that overexpression of Poly GR in mice is sufficient to induce cytoplasmic aggregation of full length TDP-43. Additionally, in collaboration with the Shorter lab, they observed that Poly GR can directly influence the aggregation of TDP-43 in vitro.

How do you think the results of this study might impact future approaches to the treatment of ALS?

These studies have begun to unravel the mechanisms by which TDP-43 aggregation occurs in the context of C9orf72 disease. While future experiments are necessary to determine the biological effects of the aggregates themselves, these studies have also shown that reduced expression of the C9orf72 repeat expansion can significantly mitigate multiple molecular hallmarks of disease including TDP-43 aggregation. A continued investigation into the pathways and proteins that influence TDP-43 mislocalization and subsequent aggregation is likely to provide insight into additional therapeutic strategies for the treatment of neurodegenerative diseases characterized by TDP-43 pathology.

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