Project 458227

Spinal muscular atrophy (SMA) is a devastating genetic childhood neurodegenerative disorder caused by the degeneration of lower motor neurons. Motor neurons connect the spinal cord to muscle, allowing for movement, feeding and breathing. SMA patients suffer from progressive muscle weakness, leading to complications such as scoliosis, respiratory failure, and early death. SMA is caused by the loss of the Survival Motor Neuron (SMN1) gene. This gene produces a protein called the Survival Motor Neuron (SMN) protein, but the specific role of SMN is unknown. SMA has been historically regarded as a motor neuron disorder, but growing evidence suggests that multiple tissues are affected in the disease. We have extensively characterized fatty acid metabolism defects present in SMA patients and our Smn2B/- mouse model of SMA. Interestingly, liver-specific restoration of SMN is capable of rescuing the fatty liver in Smn2B/- mice, indicating that these defects are caused by liver specific processes. We aim to identify the underlying molecular mechanisms behind these liver specific defects. We will therefore perform RNA sequencing of Smn2B/- mouse livers. RNA data will allow us to determine which genes are being dysregulated due to the loss of SMN, and uncover the molecular basis for liver-specific defects. We will then validate our results by restoring a gene of interest in our mice, and assessing the benefit of this treatment on liver defects. The results from this study will allow for a better understanding of liver disease in SMA, and potentially identify a therapeutic target. As growing evidence establishes SMA as a multi-organ disease, it is clear that each cell and tissue type must be investigated in order to understand its individual contribution to disease. The identification of the molecular basis for liver pathogenesis will allow for the development of effective therapies and lifestyle changes that will have a positive impact on SMA patients' health and wellbeing.