
Amanda S. 2025 | BASIS Independent Silicon Valley
- Project Title: Consequences of Alternative Polyadenylation (APA) on Frontotemporal Dementia and Amyotrophic Lateral Sclerosis upon TDP-43 Knockdown.
- BASIS Independent Advisor: Karen Allendoerfer
- Internship Location: Stanford University
- Onsite Mentor: Stephanie (Steph) Rayner; postdoc; Stanford University
In the majority of ALS patients and around half of FTD patients, the protein TDP-43 is found maladaptively depleted from the nucleus and aggregated in the cytoplasm. Recent research has shown TDP-43, which is involved in various levels of RNA regulation, to be essential in regulating alternative polyadenylation (APA). Its loss leads to widespread APA changes. APA is a gene regulation process involving the usage of different polyadenylation (polyA) sites and is found in more than 60% of human genes. Its occurence could lead to RNA sequences with different 3’-UTR lengths, potentially impacting protein levels, as binding to distal polyA sites leads to longer 3’ UTRs compared to proximal polyA sites. For this project, I will be studying these mechanisms within the gene TMEM106B, a key genetic risk factor in FTD/ALS, at the Gitler Lab, where Dr. Yi Zeng and colleagues have recently identified widespread polyadenylation changes that occur in cases of FTD with TDP-43 pathology. TMEM106B encodes for the lysosome transmembrane protein TMEM106B and often also forms polymorphic dimers with itself (“homodimers”), with high levels protecting against the diseases and lower levels leading to increased risk. When TDP-43 is depleted, APA occurs in the TMEM106B transcript, resulting in a lengthening of its 3’ UTR. My research will aim to examine how changes in polyA site usage in the 3’-UTR upon TDP-43 knockdown contribute to the molecular expression of TMEM106B and how this could impact transcript protein interaction partners or protein interaction partners. Specifically, I will be conducting wet lab experiments using a neuronal cell model to determine how TMEM106B’s protein interaction partners differ between short vs. long isoforms. This research will provide new molecular insights into the mechanisms by which FTD/ALS develop that may contribute to the advancement of future therapeutics.