Gasdermin-D assembly at mitochondria facilitates the propagation of sterile neuroinflammatory responses in alpha-synucleinopathy

Active Project Grant Awarded Last action

Award ID
F31AG104731
Recipient
Awarding agency
Obligated
$40,117

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Place of performance
Cleveland, OH 44195, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Progressive neuronal accumulation of aggregated alpha-synuclein (ΑSYN) is the major pathophysiological feature of neurodegenerative diseases known as alpha-synucleinopathies. Examples of these include parkinson's disease (PD) and dementia with lewy bodies (DLB). These disorders are hallmarked by mitochondrial dysfunction and chronic brain inflammation. However, the signaling mechanisms that facilitate the crosstalk of these processes remain under-characterized. Previous work has shown that sterile neuroinflammation-mediated mitochondrial dysfunction can activate innate-immune signaling mechanisms such as the NOD-like receptor protein 3 (NLRP3) inflammasome and the stimulator of interferon genes (STING) complex within microglia, the resident immune cells in the brain. This leads to neuroinflammation-mediated neurotoxic responses in ΑSYN models. IT remains unknown how NLRP3/STING responses directly or indirectly contribute to the spread of sterile neuroinflammation and neurodegeneration. Gasdermin-D (GSDMD) is a protein that is activated/cleaved downstream of NLRP3 inflammasome assembly and is best associated with an inflammatory cell death mechanism known as pyroptosis, where IT forms pores in the cell membrane. My preliminary data using cultured primary microglia, within the ΑSYN pre-formed fibril (PFF) model, indicates that cleaved GSDMD (CL-GSDMD) accumulates at the mitochondria and amplifies mitochondrial damage within microglia. Therefore, the central hypothesis of this proposal is that following microglial NLRP3 inflammasome assembly, GSDMD is cleaved and accumulates within mitochondria, serving to amplify mitochondrial damage and neuroinflammatory responses. To accomplish this, I will be trained in asyn-PFF modeling, mouse behavioral assays, as well as microglial inflammasome biology in the laboratory of DR. Nikhil panicker at the cleveland clinic research institute. Recent work indicates that metabolically active mitochondria can be exported from one cell to another, in a process called horizontal mitochondria transfer. This process has been implicated in several systems, where IT has been shown to increase survival and dampen inflammation in recipient cells. Current research has yet to address what happens when dysfunctional mitochondria are transferred to a recipient cell. My preliminary data indicate that CL-GSDMD-laden mitochondria can be horizontally transferred from donor to recipient cells, mediating the propagation of neuroinflammatory signaling. Therefore, I seek to elucidate how neuroinflammatory responses can spread within alpha-synucleinopathies via GSDMD-laden mitochondria. I will be mentored by DR. Justin lathia to investigate the methods of horizontal mitochondrial transfer and various mitochondrial metabolic assays. Horizontal mitochondrial transfer has thus far been explored as a neuroprotective mechanism in the central nervous system. Illustrating that this process can be "corrupted" by GSDMD to serve as a mechanism to spread neuroinflammation represents a paradigm shift in the field.

Quick answers

Who received award F31AG104731?

F31AG104731 was awarded to Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University by National Institute on Aging (National Institutes of Health) on March 1, 2027.

How much is award F31AG104731 worth?

$40,117 has been obligated on F31AG104731.

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