Modeling Spinal Muscular Atrophy with Patient Derived iPSCs to Characterize the Role of SMN in Cardiomyocytes and Microglia
Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. Global restoration of SMN in a SMA model mouse suggests that non-neuronal cells may contribute to the disease progression. In severe SMA, reports of cardiovascular and glia dysfunction are observed prior to the onset of motor neuron degeneration. In this dissertation, we utilize a patient-derived IPSC model to assess the role of SMN in cardiomyocytes and microglia function. The first study focuses on the role of SMN in cardiomyocyte function. Markers of heart failure, including brain natriuretic peptide (BNP), fatty acid-binding protein 3(FABP3) and creatine kinase (CK) are elevated in Type I SMA patients. We found impaired cardiovascular function in severe SMA mice and in cardiomyocytes differentiated from iPSC(s) derived from SMA patient(s). Reducing SMN levels in cardiomyocytes from control patient iPSCs slowed relaxation kinetics and calcium reuptake similar to SMA patient derived cardiac cells. Importantly, restoring SMN in iPSC derived cardiomyocytes increased calcium reuptake. Transcriptome data of whole hearts taken from juvenile SMA mice indicated a reduced level of SERCA, the key ATPase pump responsible for calcium reuptake and muscle relaxation. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through SERCA mediated intracellular Ca2+ cycling dysregulation. The second study focuses on the role of SMN in microglia. Increased microglia reactivity and small lymphoid organs have been reported in the SMA mice. How SMN deficiency affects immune cell function in SMA remains unresolved. In this study, we sought to characterize the immune cells in the CNS of SMA model mice and characterize the reactive profile of CNS resident microglia.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 18, 2021
- Accession Number
- AD1183038
Entities
People
- Guzal Khayrullina
Organizations
- Uniformed Services University of the Health Sciences