Topic: Protein Degradation

Study ubiquitin-independent targeted protein degradation for oncology in Catherine Lindon’s laboratory, in partnership with AstraZeneca. The project investigates Midnolin biology and develops binding and engineered tools that redirect its activity towards therapeutic targets. The award supports four years of doctoral research.

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that regulate gene expression, yet their molecular functions in neurobiology are unclear. While investigating neurodegeneration mechanisms using human α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg pan-neuronal overexpressing strains, we unexpectedly observed dysregulation of piRNAs. RNAi screening revealed that knock-down of piRNA biogenesis genes improved thrashing behavior; further, a tofu-1 gene deletion ameliorated phenotypic deficits in α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg transgenic strains. piRNA expression was extensively downregulated and