An enzyme-targeting approach may offer a new route to treating Parkinson’s disease and traumatic brain injury (TBI), research in mice suggests.
Parkinson’s is the second most common neurodegenerative disease and affects more than 10m people worldwide.
Current treatments address symptoms but do not prevent the underlying loss of nerve cells that drives the disease.
Investigators at University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center had previously identified a potential drug approach for neurodegenerative conditions, including Alzheimer’s disease and traumatic brain injury.
The research, led by Andrew A. Pieper and Sanford Markowitz, received the 2025 Cozzarelli Prize in Biomedical Sciences.
It found that inhibiting an immune system enzyme called 15-PGDH protected the brain by limiting the production of reactive oxygen species, unstable molecules that can damage cells.
Pieper is chair of neuropsychiatry at University Hospitals and professor of translational psychiatry at Case Western Reserve University.
He also directs the Brain Health Medicines Center at the Harrington Discovery Institute and works as a psychiatrist and investigator at the Louis Stokes Cleveland VA Medical Center.
Markowitz is a professor of cancer genetics at Case Western Reserve University and UH Seidman Cancer Center.
The researchers have now worked with Min-Kyoo Shin, a former postdoctoral trainee in Pieper’s laboratory and an assistant professor at Seoul National University, to test the approach in three mouse models of Parkinson’s.
They found similar protective effects and gained further insight into how blocking the enzyme may prevent damage.
The findings suggest that drugs being developed for other conditions could potentially be repurposed to slow or prevent neurodegeneration in Parkinson’s.
Repurposing means testing an existing or experimental medicine for a condition other than the one it was originally developed to treat.
Pieper said: “We were encouraged to see that both human Parkinson’s disease brain tissue and the brains of our three mouse models showed abnormally elevated levels of 15-PGDH.
“Both genetic and pharmacologic inhibition restored redox homeostasis, which protected mice from the neuroinflammation, neuronal cell death and motor impairment normally seen in these models of PD.”
Redox homeostasis is the balance between harmful molecules and the body’s ability to neutralise them.
Neuroinflammation is inflammation in the brain or spinal cord that can contribute to nerve cell damage.
Markowitz said: “We were excited to find that inhibiting 15-PGDH mediated neuroprotection through downregulating a trio of the dopaminergic neuronal cell death mediator lipocalin-2 (Lcn2), the pro-inflammatory cytokine interleukin-1β, and the reactive oxygen generator Cybb/Nox2.
“This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson’s disease.”
Previous work showed that an experimental inhibitor called SW033291 could penetrate the central nervous system, which includes the brain and spinal cord.
Drug levels remained in the brain and blood plasma for up to six hours, while the treatment almost completely suppressed 15-PGDH activity in the brain.
The absence of toxicity in a recent phase 1 clinical trial of another inhibitor, MF-300, also supports further investigation of the approach.
People with mutations that deactivate both copies of the gene linked to 15-PGDH have consistently shown only one observed characteristic, congenital digital clubbing.
Digital clubbing is a change in the shape of the fingers or toes that is present from birth.
Markowitz said: “Encouragingly, both pharmaceutical and biotechnology companies have initiated development of 15-PGDH inhibitors for peripheral indications, and inhibitor MF-300 has already completed Phase I clinical trials.
“Our results now provide the rationale to repurpose such agents for the treatment of PD.”
In one mouse model involving the abnormal accumulation of alpha-synuclein, the treatment protected nerve cells without changing levels of pathologically phosphorylated alpha-synuclein.
Alpha-synuclein is a protein that can build up abnormally in Parkinson’s. Phosphorylation is a chemical change associated with its disease-related form.
The finding showed that a treatment effect could be achieved without altering this aspect of alpha-synuclein pathology.
Pieper said: “This work parallels our recent finding that 15-PGDH-mediated neuroprotection in an amyloid-based Alzheimer’s disease mouse model occurred independently of changes in amyloid pathology, contributing to a growing body of evidence that potent therapeutic effect can be achieved by targeting the brain’s damage and inflammatory response to the primary drivers of disease.”
Researchers will next examine the signalling pathways through which 15-PGDH contributes to normal brain function and neurodegeneration.
They will use targeted drug and genetic experiments to explore how those pathways interact.
Further work will also investigate the mechanisms controlling Hpgd expression, which may help explain why levels of 15-PGDH rise in Parkinson’s disease.
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