The National Ataxia Foundation (NAF) is funding 20 ataxia research studies during 2016, including six projects in the United States, Italy, Canada, United Kingdom and Portugal that were provided for by the foundation’s Research Seed Money Awards.
Among the six financially seeded studies, Dr. Paul Rosenberg, an associate professor, Department of Cardiology, Duke University Medical Center, has embarked on the study “Contribution of store-operated calcium entry to calcium dysregulation in spinocerebellar ataxias.”
Rosenberg aims to understand the mechanisms responsible for neuronal calcium dysregulation, commonly found in several ataxias including the hereditary spinocerebellar ataxias. His research seeks to explain how changes in calcium are decoded by a cell in order to activate signaling pathways that control gene expression, proliferation, and metabolism.
Ataxias, a diverse group of diseases characterized by lack of coordination, are caused by a degeneration of the cerebellum, the center for motor coordination, and its connections to other regions in the brain. Purkinje neurons, found in the cerebellum, rely on significant calcium influx for their action potential. Although these cells generally fire in a steady rhythm, to encode information from the cortical cerebellum to areas of motor coordination, unhealthy Purkinje cells can fire in bursts leading to high levels of calcium in the neurons and inducing ataxic disorders marked by impaired muscle coordination.
Many ataxias, including hereditary spinocerebellar ataxias, are linked to dysregulation of neuronal calcium, which leads to the dysfunction, degeneration, and death of Purkinje neurons. The research team at the Duke University Medical Center is seeking to understand the mechanisms involved in calcium dysregulation in ataxia, which will possibly allow for the development of therapeutic strategies in this group of diseases.
The investigators will be unravelling the role of a novel calcium signaling pathway named store-operated calcium entry (SOCE), known to have a role in the regulation of calcium dynamics of Purkinje cells and other neurons in an STIM1 (a calcium sensor)-dependent manner, in the dysregulation of calcium homeostasis and pathogenesis of ataxia.
The primary hypothesis is that the disruption of the SOCE pathway contributes to the dysfunction of Purkinje cells, leading to motor deficits in a number of ataxias. To test it, researchers will employ established mouse models of several ataxias to address whether STIM1-dependent SOCE can contribute to calcium dysregulation and Purkinje cell dysfunction, and to what extent an increase or decrease in SOCE signaling can account for Purkinje cell dysfunction and degeneration in ataxia.
Researhers believe that the study will reveal a clearer understanding of the SOCE pathway in calcium-dependent degeneration of Purkinje cells in ataxia, and may lead to to the development of novel therapeutic approaches for the treatment of these diseases.
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