Anuradhika Puri

Results To select for potentiated Hsp104 variants, we co-expressed a library of randomized MD variants in yeast with TDP-43 (Figures 1A and 1B). Here, galactose induces expression of both TDP-43 and Hsp104, and yeast harboring suppressors of TDP-43 toxicity display a growth advantage.26,28,29 We harvested DNA from yeast populations before and after selection and sequenced the MD regions using the Illumina MiSeq platform.

Abstract Parkinson’s disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

Abstract Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury.