Rahul Srinivasan, PhD

Education and Training

• University of Mumbai, MBBS, 2000
• Department of Human Genetics, PhD, 2006
• Division of Biology, Caltech, Postdoctoral Fellow, 2013
• Department of Physiology, UCLA, Assistant Research Physiologist, 2016

Research Interests

• Neurodegeneration, Parkinson's disease, astrocytes and nicotine neuroprotection.
• My research focuses on developing a mechanistic understanding of neurodegeneration, with the goal of discovering novel strategies to treat neurodegenerative disorders. In this regard, I am interested in two primary areas: (1) Understanding the role of astrocytes in neurodegeneration and (2) Elucidating molecular mechanisms underlying the known neuroprotective effects of nicotine in Parkinson's disease.
• We utilize a broad range of techniques spanning the spectrum from molecules to mice. Our methods include stereotaxic injections of adeno-associated viruses (AAVs) into the mouse brain, advanced imaging techniques such as Ca2+ imaging in live brain slices using genetically encoded calcium sensors (GCaMPs), in vitro and slice electrophysiology, advanced molecular biology, including creation of transgenic mice and tissue culture.
• he role of astrocytes in neurodegeneration. Astrocytes tile the entire CNS and outnumber neurons, however, their roles in neuronal physiology and pathology are not well understood. A better understanding of the role of astrocytes in Parkinson's disease should broadly enable the development of novel strategies to treat neurodegenerative disorders. To this end, we employ cutting edge tools and techniques to systematically study the morphology, physiology and functional consequences of substantia nigra pars compacta (SNc) astrocytes on dopaminergic neurons under normal conditions and in mouse models of Parkinson's disease.
• Mechanisms of nicotine neuroprotection in Parkinson's disease. Tobacco use is inversely correlated with the risk of developing Parkinson's disease (PD), but mechanisms underlying this effect remain to be elucidated. In smokers, nicotine is assumed to act via "outside-in" pharmacology, in which the drug binds to and activates neuronal nicotinic acetylcholine receptors (nAChRs) on the plasma membrane, resulting in Ca2+ influx and consequent second messenger signaling. This fails to explain neuroprotection because the steady-state plasma nicotine concentration (~100 to 200 nM) achieved in smokers cannot activate nAChRs. We suggest an alternative "inside-out" mechanism for nicotine neuroprotection that does not involve nAChR activation. We have shown that during this process, nanomolar, sub-activating concentrations of nicotine are sufficient to reduce endoplasmic reticulum (ER) stress in dopaminergic neurons via binding to and chaperoning neuronal nicotinic acetylcholine receptors (nAChRs) through the cellular secretory pathway. We are currently studying pharmacological chaperoning in mouse models of Parkinson's disease.