Noah Weisleder

Plasma membrane repair is an essential cellular mechanism that reseals membrane disruptions after a variety of insults, and compromised repair capacity can contribute to the progression of many diseases. Neurodegenerative diseases are marked by membrane damage from many sources, reduced membrane integrity, elevated intracellular calcium concentrations, enhanced reactive oxygen species production, mitochondrial dysfunction, and widespread neuronal death. While the toxic intracellular effects of these changes in cellular physiology have been defined, the specific mechanism of neuronal death in certain neurodegenerative diseases remains unclear. An abundance of recent evidence indicates that neuronal membrane damage and pore formation in the membrane are key contributors to neurodegenerative disease pathogenesis. In this review, we have outlined evidence supporting the hypothesis that membrane damage is a contributor to neurodegenerative diseases and that therapeutically enhancing membrane repair can potentially combat neuronal death.

Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by pathogenic variants in the DYSF gene. While several animal models of dysferlinopathy have been developed, most of them involve major disruptions of the Dysf gene locus that are not optimal for studying human dysferlinopathy, which is often caused by single nucleotide substitutions. In this study, the authors describe a new murine model of dysferlinopathy that carries a nonsense mutation in Dysf exon 32, which has been identified in several patients with dysferlinopathy. This mouse model, called Dysf p.Y1159X/p.Y1159X, displays several molecular, histological, and functional defects observed in dysferlinopathy patients and other published mouse models. This mutant mouse model is expected to be useful for testing various therapeutic approaches such as termination codon readthrough, pharmacological approaches, and exon skipping. Therefore, the data presented in this study strongly support the use of this animal model for the development of preclinical strategies for the treatment of dysferlinopathies.