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The role of lysosomal impairment in trichloroethylene induced Parkinsonian neurodegeneration

Award Number: R01ES034846
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/25/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The role of lysosomal impairment in trichloroethylene induced Parkinsonian neurodegeneration - Project Summary Parkinson’s disease (PD) is a systemic, progressive neurodegenerative movement disorder and type of synucleinopathy characterized by the presence of misfolded α-synuclein (αSyn) protein aggregates (Lewy bodies). The majority of PD etiology is not well explained by inherited genetic risk variants, and conversely, is strongly tied to exposure to environmental contaminants, particularly industrial byproducts such as pesticides, metals, and organic solvents. Data from our lab indicates that exposure to environmental toxicants associated with PD risk impairs the autophagy-lysosomal pathway (ALP), causing aberrant proteostasis and cellular dysfunction that influences disease development. Furthermore, new data suggests that the PD associated genetic risk factor and kinase protein LRRK2 plays a key role in lysosomal homeostasis, which implicates the lysosome as a convergence point for genetic and environmental risk factors in PD. The chlorinated organic solvent trichloroethylene (TCE) is associated with 2-6 times elevated risk for PD, however, the mechanisms by which this occurs remain vastly understudied considering the pervasiveness of its environmental contamination. We previously showed that exposure to TCE induced endolysosomal deficits, endogenous αSyn accumulation, and dopaminergic neurodegeneration in adult rodents. We also observed that TCE elevated the kinase activity of wildtype LRRK2 in the brain. In line with this, we have new preliminary evidence that TCE exposure causes loss of lysosomes, reduced proteolysis in dopaminergic neurons and significantly worsens αSyn preformed fibril (PFF) accumulation in brain tissue of adult rats. Thus, we hypothesize that an important mechanism of TCE is disruption of lysosomal function, leading to proteostasis impairment and neurotoxicity that triggers or facilitates PD development. This proposal is designed to uncover the mechanisms of TCE-induced lysosomal impairment, aberrant proteostasis, and dopaminergic neurodegeneration associated with PD risk. To do this, we will use our novel, environmentally relevant TCE inhalation model to measure how the solvent modulates αSyn PFF aggregation within the rat brain (Aim 1), and if loss of lysosomal function in central and peripheral neurons using newly developed Thy1-RFP-GFP-LC3 transgenic mice correlates with αSyn seed amplification signal measured via RT-QuIC (Aim 2). Last, we will assess how TCE-induced LRRK2 kinase activation influences lysosomal function and if pharmacological inhibition of LRRK2 prevents lysosomal impairments and neurodegeneration induced by TCE (Aim 3). Together, these experimental aims support a fundamental new mechanism in the risk for PD and related synucleinopathies from environmental factors and advances the NIEHS strategic plan to improve human health though environmental exposure research.


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 = $536,966 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	001	3	1/13/2026	SUPPLEMENT FOR EXPANSION	$122,700
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	3	12/19/2025	NON-COMPETING CONTINUATION	$414,266
														Subtotal = $536,966

Issue Date FY: 2025 ( Subtotal = $570,943 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	2	12/13/2024	NON-COMPETING CONTINUATION	$448,243
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	001	2	12/16/2024	SUPPLEMENT FOR EXPANSION	$122,700
														Subtotal = $570,943

Issue Date FY: 2024 ( Subtotal = $515,923 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	1	2/21/2024	NEW	$515,923
														Subtotal = $515,923

Grand Total All Awards = $1,623,832

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The role of lysosomal impairment in trichloroethylene induced Parkinsonian neurodegeneration

Award Number: R01ES034846

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/25/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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