Changes in the Expression of the Alzheimers Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction
A. Li, C. Zhou, J. Moore, P. Zhang, T.-H. Tsai, H.-C. Lee, D. M. Romano, M. L.McKee, D. A. Schoenfeld, M. J. Serra, K. Raygor, H. F. Cantiello, J. G. Fujimoto and R. E. Tanzi
Affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital,114, 16th Street, Charlestown, MA 02129, USA.
Mutations in the presenilin genes cause the majority of early-onset familial Alzheimers disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.
Keywords: Alzheimer's disease, calcium channel, cardiomyopathy, Drosophila, heart, presenilin, PSEN1, PSEN2, A42, A40, DCM, allelic heterogeneity, OCT, EDD, ESD
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