Scientists have long suspected that mitochondria—cellular structures responsible for producing energy—play a central role in Parkinson’s disease. But one question has remained unresolved: does mitochondrial failure drive the disease, or does it occur only after neurons begin to die?
A new study from Gladstone Institutes offers some of the clearest evidence to date that disrupted mitochondrial function can initiate Parkinson’s, not merely accompany it.
The findings, published in Science Advances, are based on a mouse model that mimics a rare inherited form of Parkinson’s caused by mutations in the mitochondrial protein CHCHD2.
Although uncommon, this genetic variant is clinically indistinguishable from the far more prevalent sporadic form, which represents about 90% of cases. Researchers say this alignment strengthens the relevance of their results for understanding typical, late-onset Parkinson’s disease.
“This mouse model provides some of the most compelling evidence to date for how mitochondrial dysfunction can cause typical late-onset Parkinson’s,” said Ken Nakamura, MD, PhD, the study’s senior author and an investigator at Gladstone. “Ultimately, defining this link may reveal new drug targets to prevent or treat the disease.”
Parkinson’s affects more than 1 million people in the United States, with most diagnoses occurring after age 60. The condition stems from the gradual loss of dopamine-producing neurons, leading to tremors, rigidity, and gait problems. But the biological pathways that drive its onset vary widely, reflecting a mix of genetic and environmental factors.
Past efforts to model these pathways in animals have often fallen short. Many mouse models carrying mitochondrial mutations associated with Parkinson’s fail to develop the hallmark features seen in human patients. The new CHCHD2 mutant model, however, recapitulates the progressive mitochondrial deterioration and protein aggregation observed in both inherited and sporadic disease.
Using this model, researchers tracked a sequence of cellular events. First, the mutated CHCHD2 protein accumulated inside mitochondria, causing them to swell and lose structural integrity. As the organelles faltered, cells shifted from efficient energy production to less effective metabolic pathways. This shift increased oxidative stress through a buildup of reactive oxygen species (ROS)—unstable molecules that damage proteins and membranes.
The rise in ROS preceded the formation of alpha-synuclein aggregates, the protein clumps that form Lewy bodies and are considered a pathological hallmark of Parkinson’s. “Alpha-synuclein doesn’t accumulate until after levels of reactive oxygen species rise,” said co-first author Szu-Chi Liao, PhD, now at UC San Francisco. “This sequence supports our hypothesis that oxidative stress drives alpha-synuclein aggregation.”
To test whether this mitochondrial cascade also occurs in people with sporadic Parkinson’s, the team collaborated with researchers at the University of Sydney. Examination of postmortem brain tissue showed that CHCHD2 accumulated in early alpha-synuclein aggregates within vulnerable dopamine neurons—mirroring the results seen in the mouse model.
“This work is a blueprint for how a mitochondrial protein can be disrupted and actually cause Parkinson’s disease,” Nakamura said. He noted that other factors may trigger the same chain of mitochondrial dysfunction, energy failure, oxidative stress, and pathological protein buildup.
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