Subhash Sinha, Ph.D.Research Associate Professor
Laboratory of Molecular and Cellular Neuroscience
Dr. Sinha is developing chemical tools and therapies for the analysis, detection and treatment of neurological disorders, including Alzheimer’s disease and major depressive disorder — in particular, novel synthetic compounds and natural product derivatives designed to target γ-secretase and γ-secretase activating protein. An aspartate protease, γ-secretase catalyzes proteolysis of the amyloid-β precursor peptide producing amyloid-β peptides, mainly comprised of 40 or 42 amino acid residues, while γ-secretase activating protein expression is directly linked to γ over ε cleavage. Amyloid-β peptides accumulate extracellularly as plaques in the brain when the monomeric peptides misfold and form a sheet. Recently, the amyloid-β pathway has also been linked to the development of tau pathology, which forms neurofibrillary tangles intracellularly and is another pathway to neurodegeneration.
Dr. Sinha and his colleagues are also developing additional compounds as chemical tools to examine and better understand the interaction between p11 proteins and serotonin receptors. Evaluation of the potential synthetic therapeutic agents and biochemical studies with the chemical tools are being performed in collaboration with Paul Greengard, who discovered γ-secretase activating protein and its interaction with γ-secretase, as well as its effects on γ-secretase catalytic activity. Dr. Greengard’s lab has identified lead compounds targeting the enzyme and its activating protein without affecting other biochemically important transformations, such as Notch cleavage. Optimal compounds will target γ-secretase and γ-secretase activating protein with high affinity and have minimal or no effects on Notch cleavage and other nonrelevant targets.