# Protein Aggregation and Inflammasome Signaling in Manganese Neurotoxicity.

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2020 · $329,840

## Abstract

Abstract
Metal exposure has increasingly been recognized as a potential environmental contributor to chronic
neurodegnerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD). Chronic
manganese (Mn) exposure has been implicated in Parkinson's-like neurological conditions in humans. Protein
aggregation and its prion-like propagation are now considered the central pathophysiological mechanisms of
many neurodegenerative diseases collectively known as proteinopathies. However, the role of metals in
protein aggregation and the neurotoxicological mechanisms that drive degenerative processes are not well
understood. α-Synuclein (αSyn) protein aggregation has been implicated in PD, and this protein features
multiple divalent metal-binding motifs that have been suggested to play a role in αSyn's fibrillization and
neurotoxicity. Since Mn shows affinity to the metal binding sites in αSyn, we have examined the effect of Mn on
αSyn in neuronal models. Interestingly, we found that αSyn protected against Mn-induced neurotoxicity during
early stages of Mn exposure, but prolonged Mn exposure promoted αSyn aggregation. In agreement with the
emerging concept that aggregated proteins propagate cell-to-cell via exosomal release, we also observed
enhanced release of exosomes containing αSyn into the extracelluar environment during Mn exposure. Thus,
our exciting finding of Mn-induced αSyn aggregation and release of exosomes with αSyn cargo prompts us to
further characterize the cellular and molecular mechanisms of neurodegenerative processes in Mn
neurotoxicity. Our proposal will test the novel hypothesis that Mn exposure promotes αSyn misfolding and
impairs intracellular αSyn trafficking, thereby increasing the formation and release of exosomes containing
αSyn protein aggregates, which subsequently trigger microglial activation through the NLRP3 inflammasome
pathway in a PKCδ-dependent manner. Sustained activation of the PKCδ-dependent NLRP3 inflammasome
pathway contributes to Mn neurotoxicity. Specific objectives of the proposal are i) to characterize the cellular
mechanism of Mn-induced impairment in endosomal trafficking, retromer dysfunction and exosome release in
cell culture and animal models of Mn neurotoxicity, ii) to determine NLRP2/3 inflammasome neuroinflammatory
signaling in microglia and astrocytes triggered by Mn-induced exosomal αSyn aggregates and to characterize
the proinflammatory regulatory function of PKCδ in NLRP2/3 inflammasome activation in Mn neurotoxicity, and
iii) to examine the role of PKCδ in mediating the exosomal αSyn aggregate-induced proinflammatory response
in animal models of Mn neurotoxicity and to confirm the presence of αSyn protein aggregation in Mn-exposed
human brain tissues. Our integrated cellular and molecular approach to unraveling the formation and release of
exosomal αSyn aggregates and their functional consequences on neuroinflammatory signaling in manganese
metal neurotoxicity will provide novel...

## Key facts

- **NIH application ID:** 10508354
- **Project number:** 7R01ES026892-06
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Anumantha Gounder Kanthasamy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,840
- **Award type:** 7
- **Project period:** 2021-12-16 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508354

## Citation

> US National Institutes of Health, RePORTER application 10508354, Protein Aggregation and Inflammasome Signaling in Manganese Neurotoxicity. (7R01ES026892-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10508354. Licensed CC0.

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