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May 18
2020

Research Bit: Molecular converging of ALS mechanisms

Research Bits
The Packard Center welcomed Michael Ward from the National Institutes of Health to a recent Investigator's meeting

Meeting Date: May15,  2020

Presenter: Michael Ward, MD, PhD

Talk Title: Molecular convergence of ALS mechanisms

What was the question being asked?

Since TDP-43 is clearly involved in ALS, either contributing to the disease progression or serving as a marker that cells are diseased, what other genes contribute to the death of neurons when TDP-43 is not functioning properly?

Why is this important for ALS research?

TDP-43 is a protein involved in many processes within human cells. In ~97% of ALS cases, TDP-43 is clumped in the cytoplasm of some neurons, and is NOT present in the nucleus, where it should be. However, for sporadic ALS cases, it is not known how this mis-localization of TDP-43 contributes to cell death. One possibility is that in each patient with sporadic ALS, there is also some other gene that is not functioning properly. Each patient may have a different gene that isn’t working, which when paired with the improper localization of TDP-43, leads to the degeneration of their motor neurons. The presented work serves to identify the genes that lead to neuronal death when TDP-43 is also not functioning.

What was the take-home message?

There are many genes that synergistically lead to neuronal degeneration with malfunctioning or absent TDP-43, and these combinations can be studied in the future to understand how sporadic ALS occurs in the absence of inherited mutations.

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

This project represents an unbiased approach to help determine which genes contribute to degeneration of neurons in sporadic ALS, which can’t be linked to any specific inherited ALS mutation. The list of ALS-contributing genes that were identified will allow other labs to study how those genes are altered in their own models for studying ALS.

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