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Apr 22

Research Bit:Validation of TDP-43 splicing repression for ALS-FTD and Inclusion Body Myositis

Research Bits
The Packard Center welcomed Phil Wong from Johns Hopkins University to a recent investigator's meeting

Meeting Date: April 17, 2020

Presenter: Phil Wong

Talk Title: Validation of TDP-43 splicing repression for ALS-FTD and Inclusion Body Myositis


What was the question being asked?

In nearly all cases of ALS a protein called TDP-43 is dysregulated. Splicing, a critical function of TDP-43, helps to maintain proper RNA homeostasis, protein production, and overall cellular function. The Wong lab hopes to determine whether disruption of the splicing function of TDP-43 drives degeneration.

Why is this important for ALS research?

TDP-43 is a major pathological hallmark in over 97% of ALS cases. While predominantly found in the nucleus, in disease, it is infrequently observed to be accumulated in the cytoplasm of neurons in postmortem tissue. However, more frequently, a nuclear clearance of TDP-43 is observed whereby TDP-43 is lost from the nucleus without accumulating into inclusions in the cytoplasm. As a result, it is hypothesized that the loss of TDP-43’s nuclear functions (including splicing) may underlie pathogenic events that precede the formation of cytoplasmic inclusions observed in end stage disease.

What was the take-home message?

Loss of TDP-43’s splicing function is prominently seen in neurons in multiple neurodegenerative diseases, including ALS, even without the formation of TDP-43 positive cytoplasmic inclusions. Moreover, the Wong lab has begun to develop viral delivery-based therapeutic strategies to mitigate splicing deficiencies.

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

The work being conducted in the Wong lab has identified a potential new therapeutic target for ALS and other neurodegenerative diseases characterized by nuclear clearance of TDP-43. Their work elegantly uncovered the basic biology of TDP-43 mediated disruptions to one key aspect of RNA processing, but has now evolved towards developing novel ideas for therapeutic modulation of this process. They also seek to develop new biomarkers in order to aid in further testing of their therapeutic strategies.

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