Ca2+ related mechanisms of cellular dysfunction in neurodegeneration

Calcium is a pleiotropic intracellular messenger regulating mitochondrial bioenergetics and proteostasis, both altered in Alzheimer’s disease (AD). In my PhD project I have studied the cause-effect relationships between calcium dishonesties and cellular dysfunction in astrocytes. In this context I investigated the discrepancy, described in AD astrocytes, between deficient mitochondrial calcium uptake and increased ER-mitochondria interaction, which in principle should promote ER-mitochondrial calcium transfer. To solve this issue, I investigated the correlation between ER-mitochondria distances and efficiency of calcium transfer: I designed a palette of ER-mitochondria linkers, discovering that ER-mitochondria calcium transfer is strongly inhibited at 10nm distances, and is strongly potentiated at 20nm, explaining why increased ER-mitochondria interaction at 8-10nm, in AD astrocytes, results in reduced mitochondrial calcium uptake. Another aspect of my PhD thesis is the investigation of Calcineurin (CaN) role in both physiology of astrocytes and AD related astrocytes dysfunction. In astrocytes, eIF2α-mediated protein synthesis and proteasomal degradation are under CaN control. While, in and AD mice model, deletion of astroglial CaN displayed a protective effect, reducing memory impairment, aβ plaques deposition and tau hyper-phosphorylation. These results indicate that CaN, under pathological conditions can drive pathology progression. I demonstrated that ER-mitochondria interaction and calcineurin represents promising therapeutic targets to mitigate AD related astroglial pathophysiology, given the importance of astrocytes for brain functions further studies are warranted to elucidate mechanisms of these dysfunctions.