Mitochondrial Dysfunction Enough to Cause Parkinson’s in Mice

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Mitochondrial dysfunction in dopamine-producing brain cells is sufficient to cause Parkinson’s disease, according to a new study done in mice.

The study, “Disruption of mitochondrial complex I induces progressive parkinsonism,” was published in Nature.

Parkinson’s is caused by the death and dysfunction of dopamine-producing (dopaminergic) neurons. A neuron, or nerve cell, consists of a cell body or soma — the part of the cell that houses its nucleus and DNA — as well as a long, fiber-like projection called an axon, which can reach away to far-off neurons and communicate with them by releasing signaling molecules like dopamine.

For decades, the scientific understanding of Parkinson’s has been that the disease develops when these neurons have axon damage, so they also are unable to send dopamine-based signals.

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Mitochondria are the so-called “powerhouses of the cell.” These sub-cellular structures are critical for generating energy, among many other essential roles. A large body of evidence has indicated that dopamine-producing neurons in Parkinson’s disease tend to have dysfunctional mitochondria. However, it has not been clear whether this is a cause or a consequence of the disease.

To gain insight, a team of researchers in the U.S. and Spain engineered mice whose dopaminergic neurons lacked a specific gene called Ndufs2, which is important for mitochondrial function. The scientists conducted a battery of assessments analyzing the mice’s behaviors as they grew, and detailing the accompanying changes in their brain biology.

Through weaning, Ndufs2-null mice were “indistinguishable” from littermates with functional mitochondria, the researchers reported. However, as the mice aged, abnormalities became evident. The mice exhibited difficulty with fine motor coordination and memory. At the same time, analyses in the mice’s brains suggested increasing dysfunction of dopaminergic neurons.

Notably, treatment with levodopa — a standard Parkinson’s treatment that basically works by giving the brain more material with which to make dopamine — eased some of these abnormalities.

Collectively, the researchers concluded that the mice “manifest clear, levodopa-responsive parkinsonism that is attributable to [mitochondrial] dysfunction.” This suggests that mitochondrial dysfunction in dopaminergic neurons is sufficient to cause Parkinson’s, they added.

Analyses of the mice’s brains over time showed that dopaminergic neuron dysfunction occurred in stages. First, the axons were impaired, and the impairment then slowly spread up to the soma.

Notably, in the early stages, when only axons were impaired, the mice showed “deficits in associative motor learning and fine sequential motor tasks, but not the gross motor impairment characteristic of” Parkinson’s, the researchers wrote.

Full Parkinson’s-like disease did not develop until both the axons and soma were affected, which challenges the longstanding idea that Parkinson’s is driven mainly by axon dysfunction. The result implies that more complex systems are at play, which will need to be further explored.

“The ultimate goal is to better understand the pathophysiology of Parkinson’s disease and contribute with this knowledge to the development of novel therapies that will improve the quality of life and life expectancy of patients,” Patricia González-Rodríguez said in a press release. González-Rodríguez is a researcher at the Institute of Biomedicine of Seville in Spain and co-author of the study.

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