Identification of Genetic Regulator of TDP-43 patient mutation mediated Cytosolic Aggregation

Authors

• BM Jones
• Y Chen
• K Cheng
• W Zheng
• C Chen
• Q Zhang

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders that share a common pathological hallmark: the cytosolic aggregation of the RNA-binding protein TDP-43 in neuronal cells. A mutation in TDP-43, specifically K181E, was identified to significantly contribute to the disease progression in ALS and FTD patients. Expression of ALS/FTD associated K181E TDP-43 drives endogenous wildtype TDP-43 into aggregates. Thus, our study aims to elucidate the genetic regulators involved in K181E TDP-43-mediated aggregation, which is critical for understanding the underlying mechanisms of these diseases. To explore the genetic factors that regulate TDP-43 aggregation, we have engineered inducible stable cell lines that exclusively express cytosolic aggregates of TDP-43. These cell lines have been adapted to a high-throughput genetic screening platform, allowing for the systematic investigation of genetic interactions. We perform a druggable genome genetic screen mediated by siRNA knockdown to identify genes that are crucial for the formation of TDP-43 aggregates. Genes that are found to play key roles in TDP-43 aggregation could be targeted for the development of gene therapies, aiming to reduce or prevent the formation of these toxic aggregates. Ultimately, our research has the potential to uncover novel strategies for the treatment of ALS and FTD, addressing the urgent need for effective therapies for these currently incurable diseases.

Scientific Focus Area: Neuroscience

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