Calcium Signaling and Pathogenesis of Neurodegenerative Disorders: Potential Therapeutic Opportunities

Alzheimer's disease and other neurodegenerative disorders are major health and economic problems. The main emphasis on treating these disorders has been based on the idea of targeting the amyloid pathway, but these efforts have not yielded effective disease-modifying therapies. In this article, I review arguments in favor of "calcium hypothesis of neurodegeneration" that offer additional targets that may potentially be explored. The main limitation in translation of this idea to the clinic has been concern about potential side effects of calcium channel blockers and inhibitors of calcium signaling enzymes in nonneuronal tissues. I reason that recently developed positive allosteric modulators of sarco-endoplasmic reticulum calcium (SERCA) pump may be able to solve this problem and briefly review results supporting this claim. If this class of compounds is proven safe in humans in clinical trials, they would offer promising therapeutic leads for developing disease-modifying therapy for a variety of neurodegenerative disorders.