Autophagy Deficits in Lower Motor Neuron and Striated Muscle Diseases: From Genetics to Therapeutic Advances

The degradation and recycling of damaged proteins and organelles through autophagy is a vital process to maintain terminally differentiated cells under energy-demanding physiological conditions and mechanical stress. Clinical and molecular studies of numerous congenital disorders of striated muscle and inherited neuropathies have reported severe autophagy defects as an underlying pathological mechanism. In this review, we investigate the genetic mutations underlying lower motor neuron diseases, skeletal muscle dystrophies, and (cardio)myopathies and how these mutations disrupt autophagy pathways. Through an in-depth analysis of the defective step of the autophagy pathway, we propose pharmacological targets that are able to correct the autophagy defects, thereby improving disease pathology. Finally, we discuss the current limitations in the development of autophagy-modulating drugs and propose novel technologies to support this growing field. By outlining key mechanisms and targets, this review supports the development of more effective autophagy modulators for rare diseases.