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Evaluating efficacy and mechanisms of a novel manganese porphyrin in a Drosophila model of Parkinson's disease

Award Number: R15NS151714
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Evaluating efficacy and mechanisms of a novel manganese porphyrin in a Drosophila model of Parkinson's disease - Abstract Identification of events that trigger oxidative stress may lead to developing successful therapeutic interventions for neurodegenerative diseases. Excessive cellular reactive oxygen species (ROS) levels result from their overproduction and/or decreased antioxidant system capacity. Reliable measurement of specific ROS and antioxidants is challenging due to their complicated interplay and their highly reactive nature; critical elucidation of oxidative stress sources presents many obstacles and has wide-ranging implications for neurodegenerative diseases, including Alzheimer’s, Parkinson’s (PD), and other dementias. Homozygous loss-of-function parkin mutations cause a rare form of PD that shares hallmark pathophysiology with the idiopathic form. Parkin is conserved in Drosophila (park), and flies have a dopaminergic brain region that is functionally homologous to the mammalian substantia nigra, which selectively degenerates in PD patients. We reported elevated protein oxidation in mitochondria of degenerating, but not non-degenerating, dopaminergic neurons in parkin-null Drosophila. Sensitive fluorescent redox reporters revealed sustained elevated levels of hydrogen peroxide (H2O2) and transiently increased glutathione redox equilibrium (GRE) in vulnerable neuron mitochondria, but not in non-degenerating neuron mitochondria. We recently found that MnTnBuOE-2-PyP5+, (MnBuOE) a redox- active manganese porphyrin (MnP), modestly decreases parkin-null dopaminergic neuron mitochondrial H2O2 and improves motivated behavior deficits. MnPs are powerful superoxide dismutase mimetics that also catalyze protein cysteine oxidation and S-glutathionylation. MnBuOE is also being tested as a normal tissue radioprotector in clinical trials involving cancer patients undergoing radiotherapy. Here, we propose to measure brain levels of oxidized and reduced low molecular weight (LMW) thiols (e.g., cystine/cysteine) and dopaminergic neuron mitochondrial H2O2 and GRE in parkin-null flies raised on food supplemented with MnP-05, a novel MnP with an improved safety/toxicity profile and brain-targeting properties compared to MnBuOE. We hypothesize that MnP- 05 reduces aged parkin-null Drosophila brain LMW thiol ratios, vulnerable neuron mitochondrial H2O2 levels and GRE. We also hypothesize MnP-05 improves parkin-null fly survival, motor behavior, and dopaminergic neurodegeneration. Restoring redox imbalances may ameliorate parkin loss-of-function pathology and warrants study of MnP-05 in additional neurodegenerative disease models toward use in clinical trials. There is currently no strategy for slowing PD progression. Despite the obvious implication of oxidative stress in PD models and patient tissue, antioxidant therapies have failed in clinical trial, perhaps because they lack critical target specificity or bioavailability.


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 = $553,721 )
2026	2026	MIDWESTERN UNIVERSITY	19555 N. 59TH AVE ADMINISTRATION BUILDING	GLENDALE	AZ	85308	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/24/2026	NEW	$553,721
														Subtotal = $553,721

Grand Total All Awards = $553,721

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Evaluating efficacy and mechanisms of a novel manganese porphyrin in a Drosophila model of Parkinson's disease

Award Number: R15NS151714

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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