Dr. Nikhil Panicker
Name of Institution:
Cleveland Clinic Foundation, Cleveland, OH
Using IPSC models to interrogate Inflammasome-mediated pathogenesis in Parkinson’s Disease
Nikhil Panicker, PhD is an Assistant Professor in the Department of Neurosciences at the Cleveland Clinic. The Panicker Lab investigates the molecular mechanisms that drive pathology in Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and other neurodegenerative disorders, with the eventual goal of developing therapeutics that block or slow disease progression. Specifically, they study cell-death pathways in neurodegenerative diseases, and how neuroinflammation (primarily mediated by microglial cells in the brain) contributes to the pathogenesis of neurologic disorders.
Dr. Panicker obtained his PhD in the lab of Anumantha Kanthasamy at Iowa State University in 2016 where he worked on neuroinflammation in PD. He then trained as a postdoctoral fellow, and subsequently as a Research Associate in Ted and Valina Dawson’s lab at the Johns Hopkins School of Medicine. The major focus of his research was to elucidate cell-autonomous and non-cell-autonomous signaling pathways that lead to neurodegeneration in degenerative brain disorders. He was awarded a postdoctoral fellowship from the Maryland Stem Cell Research Fund in 2017, and the NIH Pathway to Independence Award (K99/R00) from the National Institute on Aging in 2020.
Dr. Panicker established his independent group at the Cleveland Clinic in Summer 2022 and is currently funded by grants from the NIH and the Department of Defense.
This project aims to understand how the immune response in the brain, particularly the activation of a protein complex called the Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome, may contribute to the spread of a-synuclein protein in PD, leading to the death of dopamine neurons.
PD is believed to progress due to the accumulation of a protein called a-synuclein. Recent studies suggest that this protein can spread from one brain region to another and act as toxic “seeds,” corrupting normal a-synuclein in neurons and spreading the disease throughout the brain. Excessive inflammation in the brain, caused by immune cells known as microglia, has been linked to PD progression. The NLRP3 inflammasome, a complex of proteins, appears to be overactivated in microglia in PD. New findings suggest that a component of this complex, called ASC, may act as a seed, attracting normal a-synuclein and accelerating its aggregation and spread.
We will use special cells created from stem cells that mimic microglia and neurons in our experiments. Our research will explore whether reducing the activation of the inflammasome within microglia can protect neurons from accumulating a-synuclein. Previous work from our lab showed that mitochondrial function (energy production in cells) can influence inflammasome activity in microglia. We will investigate whether lowering mitochondrial function in microglia leads to ASC release and whether inhibiting ASC release can prevent harmful a-synuclein aggregation in neurons. Finally, we will assess whether increasing mitochondrial function can reduce microglial inflammasome responses and rescue neuron death.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our research aims to uncover new insights into how brain inflammation contributes to the dysfunction and death of neurons in PD. This understanding could open the door to novel diagnostic and treatment approaches for this challenging neurological disorder.