Nikhil Panicker, PhD, a CADRC-affiliated researcher in the Department of Neurosciences at Cleveland Clinic, has received a five-year, $2.16 million grant from the National Institute of Neurological Disorders and Stroke (NINDS) to investigate how neuroinflammation and neurodegeneration spread in Parkinson’s disease (PD) and Lewy body dementia (LBD). Dr. Panicker will lead the project, titled "Mitochondrial Gasdermin-D Propagates Neuroinflammation and Neurodegeneration in Alpha Synucleinopathy," in collaboration with co-investigator Tatiana Byzova, PhD, also of Cleveland Clinic.

The study builds on growing evidence that microglia, the brain’s resident immune cells, contribute to neuroinflammation and neurodegeneration in PD and LBD. While previous research from Dr. Panicker’s group and others has implicated innate immune responses in these diseases, the underlying mechanisms remain incompletely understood.

Preliminary findings from the team point to an intriguing possibility. Their data indicate that Gasdermin-D (GSDMD), a protein associated with inflammasome signaling, accumulates in mitochondria within microglia in models of PD and dementia with Lewy bodies (DLB). Mitochondria are structures within cells that are responsible for producing energy. The researchers have shown that this process leads microglia to release extracellular vesicles, small membrane-bound particles that can carry material between cells. These vesicles, which the team refers to as "pyro-EVs," contain damaged mitochondria.

The newly funded project will investigate whether these microglia-secreted pyro-EVs contribute to the spread of neuroinflammation and neuronal death by transferring damaged mitochondria into neighboring microglia and neurons.

The work is designed to address several important unanswered questions in the field.

One of those questions centers on the behavior of microglia after inflammasome activation. The NLRP3 inflammasome is an innate immune signaling platform whose excessive activation has been documented in several major neurodegenerative disorders. Under normal circumstances, inflammasome activation leads to cleavage of GSDMD, which then forms pores in the cell membrane and initiates inflammatory cell death. Protein aggregates associated with neurodegenerative diseases can be particularly potent activators of this pathway.

However, diseases such as DLB, PD, and Alzheimer’s disease are not characterized by widespread microglial cell death.

Dr. Panicker’s team has found evidence that, rather than causing microglia to die, cleaved GSDMD accumulates in mitochondria. Their findings suggest that this accumulation may amplify mitochondrial damage and promote harmful neuroinflammatory responses. Understanding why inflammasome-activated microglia survive, and what they do instead, may provide important insights into disease progression.

The project will also explore a potentially new function of inflammasome signaling. Misfolded protein aggregates are known to spread throughout the brain in many neurodegenerative diseases. The researchers propose that inflammasome signaling in microglia may similarly allow neuroinflammatory responses to spread from cell to cell.

Specifically, they hypothesize that pyro-EVs containing cleaved GSDMD and damaged mitochondria may transfer damaging signals between cells, propagating neuroinflammation and neuronal death. Although pyro-EVs were recently identified in macrophages, a type of immune cell found throughout the body, Dr. Panicker’s group is the first to document these vesicles in microglia and to show that they transport damaged mitochondria between cells.

The study also seeks to expand understanding of mitochondrial transfer, a process in which mitochondria move from one cell to another. Historically, mitochondrial transfer has largely been viewed as beneficial because it can provide recipient cells with healthy mitochondria that support energy production and improve cellular health. In models of Parkinson’s disease, transfer of healthy mitochondria from microglia has been shown to reduce inflammation and protect neurons from death.

By contrast, the potential harmful effects of mitochondrial transfer have received far less attention.

Dr. Panicker and colleagues aim to determine whether mitochondrial transfer can become "corrupted," allowing damaged mitochondria to spread neuroinflammation and neuronal death. If confirmed, these findings would reveal a previously unexplored aspect of mitochondrial biology and provide new context for understanding how mitochondrial transfer influences neurodegenerative disease.

The research will be conducted at Cleveland Clinic from 2026 through 2031. By investigating how inflammasome signaling, damaged mitochondria, and pyro-EVs interact to drive neuroinflammation, the project seeks to answer fundamental questions about the mechanisms underlying Parkinson’s disease, Lewy body dementia, and related neurodegenerative disorders.