Wednesday, January 28, 2026 1/28/2026

ASC oligomerization and transmission as an initiating event for protein aggregation in Synucleinopathy Dementias

Award Number: R00AG066862
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

Group Awards By:

View Award Description

ASC oligomerization and transmission as an initiating event for protein aggregation in Synucleinopathy Dementias - Synucleinopathy Dementias (Syn-Dementias) are age related, progressive neurodegenerative diseases that are characterized by α-Synuclein (αSyn) rich neuronal inclusions called Lewy Bodies (LBs). Syn-Dementias include Dementia with Lewy Bodies (DLB), Parkinson’s Disease with Dementia (PDD), as well as a subset of Alzheimer’s Disease (AD) cases with LB pathology which constitute ~40% of AD cases. Sustained neuroinflammation (mediated primarily by microglia) and progressive αSyn aggregation are hallmarks of Syn- Dementias. We recently described the activation of the Nod Like Receptor Protein-3 (NLRP3) inflammasome in mouse synucleinopathy models and in human PD brains. The NLRP3 inflammasome is a multi-protein arm of the innate immune system which, when activated, results in the production of the cytokine interleukin-1 beta (IL- 1β), as well as oligomerized Apoptosis-associated Speck-like protein containing a Caspase Recruitment Domain (ASC), which is the adaptor protein of the NLRP3 inflammasome. It is currently unknown what pathological role inflammasome activation may play in the progression of Syn-Dementias. Our preliminary data suggests that microglia-released ASC may be taken up by neurons and may cross-seed αSyn fibrilization. The overarching goal of this proposal is to elucidate the pathological role of microglia to neuron transmission of oligomerized ASC in contributing to progressive αSyn aggregation in Syn-Dementias. We also seek to elucidate the signaling mechanisms in microglia that lead to the oligomerization and release of ASC, and the mechanisms in neurons that lead to its uptake. In Aim 1, I will perform a series of experiments including Protein misfolding cyclic amplification (PMCA) and neuron/microglia co-culture studies in microfluidic chambers to support our preliminary findings. These experiments will be performed in the laboratories of primary mentors Ted and Valina Dawson and project consultant Xiaobo Mao. I will also validate neuronal ASC pathology as a pathological hallmark of Syn-Dementias. This will be done in the lab of co-mentor Juan Troncoso. Aim 2 will involve assessing the effects of blocking microglia to neuron ASC transmission on neuronal αSyn pathology. In the mentored phase, I will first inhibit Caspase-1 (Casp-1), an enzyme required for ASC release from cells but not its oligomerization or recruitment to inflammasome complexes. Conditioned medium from inflammasome- activated WT and Casp1-/- microglia will be used to elicit αSyn aggregation in mouse cortical neurons. We will also seek to identify a neuronal uptake mechanism for microglia-released ASC. This will be done by utilizing unbiased receptor screening to identify and characterize novel neuronal receptors for oligomerized ASC. These set of experiments will be performed in collaborator Xiaobo Mao’s laboratory. In the independent phase of Aim- 2, I will investigate the ramifications of preventing ASC transmission by blocking its microglial release. In Aim 3, I will investigate the novel mechanism by which the E-3 ligase Parkin inhibits ASC oligomerization in microglia by ubiquitinating the inflammasome receptor NLRP3 and targeting it for proteasomal degradation. In the independent phase, I will explore how adult onset knockout of Parkin in microglia will hasten the propagation of αSyn in mouse models. In this regard, I have already generated the Parkinflx/flx/Casp1WT and Parkinflx/flx/Casp1- /- mice that I will need for these studies. My training in the biology of dementia and aging biology will be facilitated by didactic courses as well as by participation in Clinical Pathological Seminars, Dementia and Aging Symposia at the Johns Hopkins University School of Medicine and will be overseen by co-mentor Marilyn Albert. All aspects of this project are novel and have not been investigated before. This project may elucidate a novel signaling conduit through which inflammasome activatio


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	1/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $248,999 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	7/30/2024	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	4	8/4/2023	NON-COMPETING CONTINUATION	$248,999
2023	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	10/28/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $248,999

Issue Date FY: 2022 ( Subtotal = $292,464 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	3	9/12/2022	EXTENSION WITH OR WITHOUT FUNDS	$43,465
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	8/19/2022	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $292,464

Grand Total All Awards = $790,462

Top

All Categories

About

Search

Reports

Data Submission

Award Information

ASC oligomerization and transmission as an initiating event for protein aggregation in Synucleinopathy Dementias

Award Number: R00AG066862

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer