Evaluating efficacy and mechanisms of a novel manganese porphyrin in a drosophila model of parkinson's disease

The National Institute of Neurological Disorders and Stroke, a component of the Department of Health and Human Services National Institutes of Health, awarded Midwestern University $553,721 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to evaluate the efficacy and mechanisms of a novel manganese porphyrin compound in a Drosophila model of Parkinson's disease.

The research measures brain levels of oxidized and reduced low-molecular-weight antioxidants in parkin-null fruit flies to identify oxidative stress sources and assess whether the manganese porphyrin compound MNBUOE reduces hydrogen peroxide and improves behavioral deficits in degenerating dopaminergic neurons. Parkin mutations cause a rare form of Parkinson's disease that shares pathophysiology with the idiopathic form; the Drosophila model carries a conserved parkin gene loss and possesses a dopaminergic brain region functionally homologous to the mammalian substantia nigra. The research addresses fundamental mechanisms of neurodegeneration relevant to Parkinson's disease, Alzheimer's disease, and other dementias. The compound MNBUOE is also undergoing clinical trials as a normal tissue radioprotector in cancer patients receiving radiotherapy.

Performance of the work occurs in Glendale, Arizona, with a period of performance from September 1, 2026, through August 31, 2029. The award is classified as a Project Grant, a standard assistance type under the NINDS extramural research portfolio.

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.