Our laboratory's main interest is to decipher the role of Calcium signaling in aging and in synucleinopathies

How do organelles use Ca2+ to communicate with each other?

Calcium ions (Ca2+) are one of the most important second messengers across all kingdoms in the tree of life. Ca2+ signaling influences a broad range of biological events in all cells, beginning with fertilization, development, adulthood and into cell death. Within a cell, movement of Ca2+ can occur via either the plasma membrane or by the intracellular stores such as mitochondria, lysosome, Golgi and Peroxisomes. We are interested in understanding how organelles use Ca2+ to communicate to each other in health and in disease and how these events shape cellular plasticity required to respond to metabolic and environmental changes in a spatial and temporal manner.


How does Ca2+ modulate major signal transduction hubs in synucleinopathies and in aging?

Synucleinopathies are a group of neurodegenerative diseases characterized by the misfolding and aggregation of a small lipid binding protein, a-synuclein (a-syn). These devastating disorders include Parkinson Disease (PD), Multiple systems atrophy (MSA), Dementia with Lewy Bodies (DLB) and Neurodegeneration with Brain Iron accumulation.

Using a variety of approaches including genetic, biochemical and cell biological techniques across several model systems that span from the baker’s yeast, rodent primary neurons to full animal models of the disease, we have established a critical role for the Ca2+- dependent serine/threonine phosphatase calcineurin in PD. We have found that the high cytosolic Ca2+ caused by a-syn leads to persistent and elevated calcineurin activity which drives dephosphorylation of proteins such as the nuclear factor of activated T cells (NFAT) and set up a program that leads to cell death. However, low levels of calcineurin activity, such as those achieved by genetic means or low doses of the natural compound FK506, lead to dephosphorylation of a distinct subset of proteins such as the Target of Rapamycin 2 (TORC2) which protect the cells from the toxic effects of a-syn. Complete inhibition of calcineurin, however, achieved by genetic means or high doses of FK506, eliminates its ability to dephosphorylate the proteins that are involved in protection, which also leads to cell death. We call this the “Goldilocks“ effect because in the context of a-syn, too much or no activity is detrimental, but an intermediate level of activity is beneficial. Calcineurin is highly conserved and present in all eukaryotes and is the only Calmodulin- Ca2+-dependent phosphatase. Calcineurin’s “Godilocks” phosphatase activity has broader repercussions to biology besides its role in a-syn toxicity. In the brain, calcineurin is implicated in neurite extension, synaptic plasticity, memory and learning. We are interested in exploring the mechanisms by which calcineurin can achieve this Goldiclocks activity and exploring what downstream substrates are regulated by calcineurin to achieve its protective and toxic effects.

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