Colloquium Series: Dr. Christopher Donnelly, University of Pittsburgh
Molecular Genetics Colloquium Series: University College, Rm. UC 161
Mondays: Seminar, 4-5pm. Post-seminar Discussion 5-6pm.
Week 2: January 27, 2025
Speaker: Dr. Christopher Donnelly, University of Pittsburgh
Title: Context dependent TDP-43 interactions modulate pathological phase transitions and splicing function
Host: Dr. Ji-Young Youn
Abstract:
Cytoplasmic and insoluble depositions of the nuclear RNA binding protein (RBP), TDP-43, are a neuropathological feature of most Alzheimer's Disease (AD) patients (30-60%) and a hallmark of related neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The mislocalization and aggregation of this protein are cytotoxic by disrupting its nuclear RNA regulatory function and the progressive accumulation of cytoplasmic TDP-43. The consequence is disrupted RNA splicing and the generation of cryptic exons and cytoplasmic inclusions that sequester additional TDP-43 via a feed-forward mechanism. Previous work from us and others shows that aberrant liquid-liquid phase transitions contribute to the deposition of neuropathological TDP-43 inclusions modulated by interactions with RNAs or proteins and thus regulate its physiological function. For example, short RNAs that engage TDP-43 reduce pathologic interactions mediated by its intrinsically disordered regions, and long RNAs with high valency can promote TDP-43 condensation. Furthermore, protein interactions with TDP-43, such as NUP62, enriched in the cytoplasm in C9orf72 familial forms of ALS/FTLD, can promote TDP-43 insolubility. Preventing or reversing this pathology and identifying factors to restore TDP-43 function may have therapeutic benefits. Here, we hypothesize that specific protein interactors of TDP-43 are altered under pathological conditions, thus leading to TDP-43's gained toxicity and loss of function. We characterized the spatial interactomes of TDP-43 under mislocalization, impaired RNA-binding, and oxidative stress to establish the lost interactions of TDP-43 under mislocalization with mRNA splicing-related proteins. Further, we mapped TDP-43's interacting relationships with cellular biomolecular condensates (BMCs). We then screened for interactors that modulate TDP-43 loss of splicing function or phase transitions. Together, this study provides a context-dependent protein interactome of TDP-43 interactors that modulate its physiological function and aberrant phase transitions that may be of therapeutic benefit.