# Mechanisms of Manganese Neurotoxicity

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $597,445

## Abstract

PROJECT SUMMARY
Mn is an essential metal with neurotoxic properties in excess. Increasingly high exposure to manganese (Mn)
in adults is associated with subclinical parkinsonian movements and postural instability, increased risk for
Parkinson's disease (PD) or parkinsonism, and at the highest levels with manganism, a parkinsonian-like
disorder, which is not ameliorated after cessation of exposure. Developmental and childhood Mn exposures
have been associated with cognitive, behavioral as well as motor function alterations. Mn neurotoxicity involves
both direct toxicity to neurons as well as neuroinflammatory responses. Here, we propose to continue our Mn
neurotoxicity research program with a focus on the identification and mechanistic relationships of precise
molecular targets of Mn neurotoxicity with exposures proximate to the transition from replete to neurotoxic
levels of Mn – environmentally relevant dosing. We hypothesize that threshold-level Mn neurotoxicity
occurs via alteration of Mn-dependent/-activated biological functions. We will test the hypothesis as
follows: In Specific Aim 1 we will identify the mechanistic basis by which Mn alters insulin/insulin-like growth
factor (IGF) related metabolic pathway signaling in neurons and the highly interconnected mTOR (mTORC1
and mTORC2), AKT and ATM/p53 metabolic signaling systems, both in worms and mammalian systems.
Studies in Specific Aim 2 will refute or establish a mechanistic relationship between dopamine (DA)
neurobiology and the insulin/IGF related signaling pathways in Mn neurotoxicity. Finally, in Specific Aim 3, we
will define the mechanistic relationships of the insulin/IGF related signaling pathways and cellular Mn
neurotoxicity outcomes. This highly interactive experimental design brings to bear innovative and
complementary expertise to assess functional domains that regulate key nodes of interaction between Mn and
biological systems, focusing on whether the threshold-level for Mn-induced neurotoxicity occurs via alteration
of Mn-dependent/-activated biological functions. The studies are geared to address these timely objectives with
translational extrapolation from the nematode to humans.

## Key facts

- **NIH application ID:** 9977202
- **Project number:** 5R01ES010563-20
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Michael Aschner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $597,445
- **Award type:** 5
- **Project period:** 2001-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977202

## Citation

> US National Institutes of Health, RePORTER application 9977202, Mechanisms of Manganese Neurotoxicity (5R01ES010563-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977202. Licensed CC0.

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