Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of motor neurons in the spinal cord and progressive atrophy of skeletal muscle. SMA is the most frequent inherited cause of infant mortality and no treatment is currently available for the disease. SMA is caused by a deficiency in the ubiquitously expressed survival motor neuron (SMN) protein due to homozygous deletion or mutation of the SMN1 gene. Despite a clear genetic basis of the disease and progress in the knowledge of SMN biology, the molecular mechanisms of SMA are poorly understood. SMN has a well- established function in the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are critical for RNA splicing and 3' end formation of histone mRNAs. Moreover, it is becoming increasingly clear that SMN has additional functions in RNA regulation that might also contribute to SMA. However, although SMN plays a central role in post-transcriptional gene regulation, the contribution of specific SMN-dependent RNA pathways to SMA pathology remains elusive. A major challenge in SMA research is to identify which SMN-dependent RNA pathways and downstream genes among many potentially dysregulated events are directly relevant to the disease phenotype. This is critically important to elucidate the molecular mechanisms of this devastating disease and may also help to develop therapeutic approaches distinct from SMN upregulation. This project aims to determine the direct contribution of three specific and well-established SMN-dependent RNA pathways - U12 splicing, U7 snRNP biogenesis, and alternative splicing - to motor system dysfunction in a mouse model of the disease that provides the best recapitulation of the human condition both genetically and phenotypically. Our hypothesis is that specific defects in these pathways are causally linked to distinct functional abnormalities of the SMA motor system. To address this hypothesis, we will investigate both the role of disruption of each of these RNA pathways in SMA pathology and their requirement for normal motor system development using, respectively, selective restoration (Aim 1) and inhibition (Aim 2) approaches in mouse models. These studies will be combined with RNA profiling of select motor circuit neuron populations with the aim of identifying the transcriptome alterations induced by SMN deficiency that are specifically associated with each RNA pathway and their respective downstream gene targets that may directly contribute to the disease process, the functional relevance of which will be tested in SMA mice (Aim 3). Collectively, this project is designed to determine the RNA-dependent mechanisms of synaptic dysfunction and motor neuron death in SMA.
SMA is a motor neuron disease caused by ubiquitous deficiency in the SMN protein, which has multiple functions in RNA regulation. This project will determine whether disruption of three distinct RNA pathways regulated by SMN?which we have identified for their potential involvement in the disease process?contribute to SMA pathology in a well-established mouse model. These studies are designed to elucidate the molecular mechanisms of SMA and have the potential to identify new research avenues for the development of therapeutic approaches for this incurable disease.
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