Study on hnRNPA1 Pathobiology in ALS



 DESCRIPTION (provided by applicant): Mutations in hnRNPA1 are recently found in multiple families with amyotrophic lateral sclerosis (ALS). HnRNPA1 is known to regulate RNA processing and to interact with proteins related to varying cellular functions, but how hnRNPA1 mutation causes disease is not known. A critical step towards understanding hnRNPA1 pathogenesis is determining the effect of pathogenic mutation on hnRNPA1 function at both systematic and molecular levels. HnRNPA1, TDP-43 and FUS belong to ribonucleoprotein family and their mutations are all associated with ALS. The three ribonucleoproteins exhibit similarity in disease features: 1) the disease shows an autosomal dominant trait; 2) proteinopathy and mitochondrial impairment is prominent in the disease; and 3) both wildtype and mutant forms cause diseases when overexpressed in animal models. Even seven years after the discovery of TDP-43 mutation in ALS, how TDP-43 mutation causes the disease remains elusive. Our preliminary studies show that both deficiency and excess in hnRNPA1 expression causes neurotoxicity respectively in hnRNPA1 knockdown and transgenic rats, suggesting that hnRNPA1 must be tightly regulated to maintain its normal function. To unravel the effect of pathogenic mutation on hnRNPA1, we created hnRNPA1 knockin rats in which a single pathogenic mutation is introduced. The knockin rats differ from their wildtype littermates in a single nucleotide examined. Any phenotypes detected in the knockin rats must result from the pathogenic mutation. With unprecedented rat models, we will examine how pathogenic mutation impacts hnRNPA1 function at both the systematic and molecular levels, revealing the mechanism by which hnRNPA1 mutation causes neurodegeneration in ALS.