Role of HSP70 chaperone in protein aggregate phenomenon of GNE mutant cells: Therapeutic lead for GNE Myopathy.

Limited treatment options and research in understanding the pathomechanisms of rare diseases has raised concerns about their therapeutic development. One such poorly understood ultra-rare neuromuscular disorder is GNE Myopathy (GNEM) which is caused due to mutation in key sialic acid biosynthetic enzyme, GNE. Treatment with sialic acid or its derivatives/precursors slows the disease progression, but curative strategies need to be explored further. Pathologically, muscle biopsy samples of GNEM patients reveal rimmed vacuole formation due to aggregation of β-amyloid, Tau, presenilin proteins with unknown mechanism. The present study aims to understand the mechanism of protein aggregate formation in GNE mutant cells to decipher role of chaperones in disease phenotype. The pathologically relevant GNE mutations expressed as recombinant proteins in HEK cells was used as a model system for GNEM to estimate extent of protein aggregation. We identified HSP70, a chaperone, as binding partner of GNE. Downregulation of HSP70 with altered BAG3, JNK, BAX expression levels was observed in GNE mutant cells. The cell apoptosis was observed in GNE mutation specific manner. An activator of HSP70 chaperone, BGP-15, rescued the phenotypic defects due to GNE mutation, thereby, reducing protein aggregation significantly. The results were further validated in rat skeletal muscle cell lines carrying single Gne allele. Our study suggests that HSP70 activators can be a promising therapeutic target in the treatment of ultra-rare GNE Myopathy disease.