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May 20

Research Bit: Activity-dependent regulation of alternative TDP43 isoforms and their contribution to ALS

Research Bits
The Packard Center welcomed Sami Barmada from the University of Michigan to our recent Investigator's Meeting.

Meeting Date: May 17, 2019
Presenter: Sami Barmada, MD, PhD (University of Michigan)
Talk Title: Activity-dependent regulation of alternative TDP43 isoforms and their contribution to ALS

What was the question being asked?

Excessive activity of neurons has long been considered a prominent feature of ALS. While many clinical trials aim to treat increased communication between neurons, the biology underlying the phenomenon is poorly understood. Dr. Barmada and his lab have found that increased neuronal activity results in increased cell death, similar to that observed for neurons with increasing levels of TDP43, a protein widely implicated in the pathology of ALS. The Barmada lab now seeks to understand whether increased neuronal activity is tied to TDP43 pathology, which would ultimately bridge common pathological and functional alterations in ALS.

Why is this important for ALS research?

Understanding how neuronal function is disrupted and what cellular proteins are altered is essential to the identification of therapeutic strategies for ALS. The work led by Dr. Barmada will shed light on the connection between TDP43 pathology and altered neuronal function, ultimately furthering our understanding of disease pathways common to nearly all ALS patients.

What was the take-home message?

Through a series of elegant experiments, Dr. Barmada and his lab have shown that increased neuronal activity alters the regulation of TDP43 production resulting in the upregulation of a shorter version of TDP43. This in turn leads to accumulation of the short form of TDP-43 as well as the normal full length form of TDP-43, both of which can be observed in patient tissue.  

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

The identification of additional forms of TDP43 provides a potential opportunity for novel therapeutic targets and/or pathological readouts of disease once we fully understand its function and role in disease progression.

Alyssa Coyne, PhD
Postdoctoral Fellow, Rothstein Lab
Johns Hopkins University School of Medicine

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