Innovative research targets cellular powerhouses for Parkinson's treatment

A groundbreaking study spearheaded by Prof Gabriel Balmus (UK DRI at Cambridge), in collaboration with Prof David K. Simon from Harvard Medical School and biotech innovator Mission Therapeutics, has provided new insights into Parkinson’s disease and the potential to develop targeted treatments. The study's findings are published in the journal Nature Communications.

The research centres on mitochondria, the 'power plants' of cells, which are crucial for energy production and essential for normal cellular functions. In Parkinson's disease, these mitochondria can malfunction, leading to the degeneration of dopaminergic neurons—brain cells responsible for producing dopamine. The degeneration of these cells is a key contributor to Parkinson’s notorious motor symptoms, such as tremor, muscle rigidity, and movement difficulties.

Under typical conditions, cells mark dysfunctional mitochondria with a protein 'flag' called ubiquitin, signalling the need for their disposal via a process known as mitophagy. A protein named USP30 strips away these 'flags,' disrupting the clearance of malfunctioning mitochondria.

The researchers made a pivotal discovery that mice genetically modified to lack the USP30 gene were safeguarded against typical movement deficits in a mouse model of Parkinson’s. Further benefits observed included enhanced mitophagy and a reduction in dopaminergic neuron loss. Building on this, the study demonstrated that blocking USP30 with an experimental molecule—MTX325, developed by Mission Therapeutics—could be a viable treatment strategy.

"Enhancing mitophagy to remove damaged mitochondria has been shown to protect vital neuron functions," Prof Balmus remarked. "By blocking USP30 in mouse and human cells, we observed not just an increase in damaged mitochondria clearance but also protection for the neurons that are usually destroyed by Parkinson's. This research solidifies USP30 as a significant therapeutic target for developing disease-altering treatments for Parkinson's."

Dr Paul Thompson, Chief Scientific Officer at Mission Therapeutics, emphasised: "Our experimental drug, MTX325, acts by inhibiting the USP30 enzyme, thereby promoting mitochondrial quality control. This landmark paper propels us to advance our studies on USP30 inhibition as a potential paradigm shift in treating Parkinson's Disease."

Prof David K. Simon of Harvard Medical School added, “Our studies on USP30 knockout mice in a synuclein-based Parkinson's model confirm that USP30 removal is beneficial. This collaboration with Cambridge and Mission Therapeutics is crucial, and we look forward to the insights that future clinical trials will bring.”

Dr Tracy-Shi Zhang Fang, the lead author, shared an enthusiastic remark: "Observing that Parkinson’s model mice with USP30 depletion showed no motor deficits was a profound moment; it underscored that we might be on the verge of a major breakthrough in treating Parkinson’s."

Mission Therapeutics is gearing up to launch a Phase I clinical trial for MTX325 in early 2024.

To find out more about Prof Gabriel Balmus's research, visit his UK DRI profile. To keep up to date with the latest UK DRI news and events, sign up to receive our monthly newsletter.

Reference: Fang, TS.Z., Sun, Y., Pearce, A.C. et al. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nat Commun 14, 7295 (2023). https://doi.org/10.1038/s41467...

Article published: 10 November 2023
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