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Jul 10

Research Bit: Aggregation dependent and independent mechanisms of toxicity in TDP and FUS proteinopathies

Research Bits
The Packard Center welcomed Magda Polymenidou, PHD from the University of Zurich to a recent Investigator's meeting

Date: July 10, 2020

Presenter: Magda Polymenidou, PhD

Talk Title: Aggregation dependent and independent mechanisms of toxicity in TDP and FUS proteinopathies

What was the question being asked?

Work in Dr. Polymenidou’s lab seeks to understand the structure and morphology of TDP-43 and FUS protein aggregates and their impact on neuronal biology and survival. TDP-43 and FUS are RNA binding proteins that are present in postmortem aggregates in ALS patient tissue. For TDP-43 specifically, multiple morphological and structural subtypes of aggregates have been identified. The Polymenidou lab is working to address how these morphologically distinct aggregates differentially affect neuronal biology and survival.

Why is this important for ALS research?

The nuclear clearance and subsequent cytoplasmic aggregation of TDP-43 is a prominent pathological hallmark in over 97% of ALS cases and about 50% of FTD cases. Interestingly, these aggregates fall into multiple structural and morphologically distinct categories. However, to date it is unknown how this differential pathology occurs across various disease subtypes and whether aggregate subtypes can differentially affect neuronal function and survival.

What was the take-home message?

To date, the Polymenidou lab has found that TDP-43 aggregates associated with two forms of FTD, FTLD-A and FTLD-C, are not only morphologically distinct, but also differentially affect neuronal survival. Specifically, the aggregates found in FTLD-A are highly neurotoxic in comparison to those found in FTLD-C.

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

As not all TDP-43 aggregates look the same, it is likely that they may differentially affect neuronal function. Early data from the Polymenidou lab supports this idea. Thus, understanding how disease subtype specific TDP-43 aggregates affect neuronal function may provide insights into therapeutic interventions that may prove useful for specific diseases.

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