Molecular Mechanisms Underlying Muscle Wasting in Huntington's Disease.

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic expansions of the triplet cytosine-adenosine-guanosine (CAG) within the Huntingtin gene. These expansions lead to a prolongation of the poly-glutamine stretch at the N-terminus of Huntingtin causing protein misfolding and aggregation. Huntingtin and its pathological variants are widely expressed, but the central nervous system is mainly affected, as proved by the wide spectrum of neurological symptoms, including behavioral anomalies, cognitive decline and motor disorders. Other hallmarks of HD are loss of body weight and muscle atrophy. This review highlights some key elements that likely provide a major contribution to muscle atrophy, namely, alteration of the transcriptional processes, mitochondrial dysfunction, which is strictly correlated to loss of energy homeostasis, inflammation, apoptosis and defects in the processes responsible for the protein quality control. The improvement of muscular symptoms has proven to slow the disease progression and extend the life span of animal models of HD, underlining the importance of a deep comprehension of the molecular mechanisms driving deterioration of muscular tissue.