Seminar by Dr. Min Jeong Kye

Uniklinik Köln

Disturbed protein and RNA homeostasis in a genetic motor neuron disease. Spinal muscular atrophy

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. It is well described that SMA is caused by mutation/deletion of the gene, SMN1 (survival motor neurons 1) and the amount of SMN protein determines severity of the disease. As SMA is a neuromuscular disorder, we investigate the pathology of SMA in motor neurons and muscle tissues. First of all, we found that dysregulated axonal microRNA expression inhibits axonal local translation in neurons and this contributes to SMA pathology. Second, dysregulated microRNA expression in SMA motor neurons are due to the dysfunctional neuronal activity-autophagy-Drosha pathway. We identified how microRNA expression is regulated in motor neurons, and how its dysregulation contributes to neurodegeneration. Next, while SMA is primarily considered as a motor neuron disease, recent data suggests that SMN deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Taken together, SMN loss causes defects in RNA and protein homeostasis in motor neurons, via cell autonomous and non-autonomous signaling pathways.