Tuesday, August 19, 2025 8/19/2025

Identifying neuronal targets and mechanisms of manganese-induced neuromotor disease

Award Number: F31ES036908
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/16/2024
PERIOD OF PERFORMANCE END DATE: 08/15/2027

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Identifying neuronal targets and mechanisms of manganese-induced neuromotor disease - Project Summary/Abstract: Manganese (Mn) is an essential micronutrient, but in excess, it is neurotoxic. Humans who are over-exposed to Mn environmentally or occupationally develop cognitive and motor deficits. Under conditions of over-exposure, Mn builds up in the basal ganglia of the brain, which primarily contains dopaminergic or GABAergic neurons. However, the exact neural targets and mechanisms of Mn toxicity are poorly understood. A question that remains unanswered is whether Mn targets dopaminergic or GABAergic neurons of the basal ganglia to induce motor disease. In the proposed work, we use the critical Mn efflux transporter protein SLC30A10 as a tool to address this question. Homozygous loss-of-function mutations of SLC30A10 causes childhood dystonia and adult-onset parkinsonism. We previously showed that loss of SLC30A10 in the brain leads to elevated Mn levels in the basal ganglia in early-life, lifelong motor deficits, and impaired evoked dopamine release. Previous studies also revealed that selective loss of SLC30A10 in dopaminergic neurons leads to motor deficits in early-life that persist into adulthood. These findings show that activity of SLC30A10 in dopaminergic neurons is required to protect against Mn toxicity and suggest that Mn targets dopaminergic neurons of the basal ganglia. To definitively identify the neuronal targets and mechanisms of Mn toxicity, we will use dopaminergic- or GABAergic-specific Slc30a10 knockin mice. These mouse models allow us to selectively increase Slc30a10 expression in specific neurons and attenuate increased Mn levels after exposure. In the proposed work, we will use behavioral and neurochemical approaches to test the hypothesis that dopaminergic neurons are the primary target of Mn. Knockin and control mice will receive an oral Mn treatment or vehicle treatment starting from birth, and we will perform behavioral assays at various timepoints from PND28-180. Proposed experiments also include metal analyses and assaying for changes in evoked dopamine and GABA release by in- vivo microdialysis. Results from early-life behavioral assays with the dopaminergic-specific Slc30a10 knockin strain have shown that knockin mice are protected from early-life Mn-induced motor deficits after Mn exposure, compared to control littermates that develop motor deficits. These novel findings corroborate the hypothesis that Mn primarily targets dopaminergic neurons of the basal ganglia to induce motor disease. This proposed study will therefore provide valuable insight into the prevention of Mn-induced disease and inform future studies towards developing treatments.


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: 2025 ( Subtotal = $41,177 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Environmental Health	000	2	7/31/2025	NON-COMPETING CONTINUATION	$41,177
														Subtotal = $41,177

Issue Date FY: 2024 ( Subtotal = $40,613 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Environmental Health	000	1	7/19/2024	NEW	$40,613
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Environmental Health	001	1	7/19/2024	NEW	$0
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Environmental Health	002	1	7/19/2024	NEW	$0
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Environmental Health	003	1	7/19/2024	NEW	$0
														Subtotal = $40,613

Grand Total All Awards = $81,790

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Identifying neuronal targets and mechanisms of manganese-induced neuromotor disease

Award Number: F31ES036908

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/16/2024

PERIOD OF PERFORMANCE END DATE: 08/15/2027

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