Our laboratory's main interest is to decipher the role of the Ca2+-dependent phosphatase calcineurin in memory and learning under physiologic and pathological conditions
To tackle this fundamental question, we study two prominent Lewy Body Pathologies: Dementia with Lewy Bodies (DLB) and in Parkinson’s Disease Dementia (PDD). We focus on a handful of calcineurin substrates that we have retrieved from unbiased phosphoproteomic approaches and we take multidisciplinary approaches that range from biophysical, biochemical to cell biological techniques in systems that span from yeast, to primary hippocampal and cortical rodent neurons, human iPSC-derived cortical neurons to in vivo rodent models of α-synuclein pathology.
Ykt6 is an essential SNARE highly conserved throughout eukaryotic evolution. We recently found that phosphorylation regulated by Ca2+ signaling drives a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. We showed that phosphorylation is also a critical determinant for Ykt6 vesicular function activities in the secretory and autophagy pathways under normal and α-synuclein conditions. Ykt6 is highly expressed in the hippocampus and the cerebral cortex, yet its function has not been explored in these brain regions. Our current work is focused on understanding the role of Ykt6 in memory and learning under normal and in DLB and PDD-like conditions.
Neurons rely on connections made with neighboring neurons to communicate in response to diverse stimuli. These connections, achieved by the incredible complexity of their axonal trees, are therefore critical for neurons to function properly. It has recently been appreciated that the loss of axonal trees possibly determines cell specific vulnerability and ultimately drives degeneration in PD. It is also known that the proteins that are critical in building these axonal trees, GAP-43 and BASP1, are perturbed in models of PD. We have recently shown that partial inhibition of calcineurin with the FDA-approved drug Tacrolimus (also known as FK506), can prevent neurodegeneration in models of PD. Because calcineurin can regulate the activity of GAP-43 and BASP1, we are interested in understanding how calcineurin modulates the activity of GAP-43 and BASP1 to regulate endocytosis, actin dynamics and electrical responses and ultimately to contribute to the degeneration of axonal trees in models of PD.
Rat primary cortical neurons transduced with BASP-1 GFP and stained with Phalloidin in Red
Astrocytes are active regulators in the neural connectome and protect neurons against toxic insults. Excessive astrocytic activity, however, can be detrimental and is a hallmark of several neurodegenerative diseases including PDD and DLB. The mechanism that governs the transition from toxic to protective astrocytes is not well understood. Through a multidisciplinary approach we found that calcineurin activity plays a central role in the conversion from toxic to protective astrocytes by rewiring their metabolism. We are interested in understanding the mechanism that initiates this metabolic exchange as well as the signal transduction pathways that drive this symbiotic relationship.
