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

> **NIH NIH K99** · JOHNS HOPKINS UNIVERSITY · 2020 · $135,540

## Abstract

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...

## Key facts

- **NIH application ID:** 9951349
- **Project number:** 1K99AG066862-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Nikhil Panicker
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $135,540
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951349

## Citation

> US National Institutes of Health, RePORTER application 9951349, ASC oligomerization and transmission as an initiating event for protein aggregation in Synucleinopathy Dementias (1K99AG066862-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951349. Licensed CC0.

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