Defective protein translation: a causative pathway in ALS?

In the vast majority of ALS cases, there is an abnormal accumulation of a protein called TDP-43 within neurons. TDP-43 plays a crucial role in processing messenger RNA (mRNA) molecules, which serve as a genetic blueprint for protein synthesis at specific cellular structures called ribosomes. When TDP-43 moves from the nucleus (where it is normally found) to the cytoplasm, a hallmark feature of ALS, it is no longer able to perform its normal function effectively. However, the precise mechanisms underlying how TDP-43 contributes to ALS are not fully understood, making the development of effective therapies challenging.

Previous studies have indicated that a buildup of cytoplasmic TDP-43 leads to a decrease in overall protein production in cells. Research conducted in the Cashman lab highlighted a potential therapeutic role for a specific ribosomal protein called Receptor of Activated C-Kinase 1 (RACK1), as it was shown that lowering RACK1 levels can reduce TDP-43 accumulation in the cytoplasm, partially relocate TDP-43 back to the nucleus, and restore normal protein production within cells. These findings suggest a novel disease mechanism whereby TDP-43 pathology is mediated by RACK1.

With this award, Amrita aims to delve deeper into the relationship between RACK1 and TDP-43 in ALS. Her research will focus on understanding how reduced RACK1 levels promote the restoration of protein production in cells and whether lowering RACK1 expression in fruit fly models of ALS can prevent neurodegeneration. The outcomes of this study could lay the groundwork for exploring RACK1-based therapies for ALS in the future and improve our understanding of mechanisms related to TDP-43 pathology, the specific role of RACK1 in ALS, and more broadly shed light on protein production defects in neurodegenerative diseases.