AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis

Abstract

Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.