Imbalances in protein homeostasis caused by mutant desmin

Abstract

Mutations of the human desmin gene on chromosome 2q35 cause autosomal-dominant and -recessive myopathies and cardiomyopathies. For pathophysiological and therapeutic studies, we generated and characterized R349P desmin knock-in mice, which serve as patient-mimicking disease models for desminopathies. By crossbreeding our desminopathy with p53 knock-out mice, we generated immortalized desminopathy myoblast cell lines. We used these myoblasts in conjunction with skeletal muscle tissue from the desminopathy mice to study the effects of R349P mutant desmin on the ubiquitin-proteasome system, bulk autophagy, chaperone-assisted selective autophagy, and heat shock proteins.