New research upends principles of Parkinson’s disease onset

Reuters Health - 11/11/2021 - Damage to mitochondria in dopaminergic neurons can trigger Parkinson's symptoms in mice, according to a new study that might end a long-running debate.

"This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurons is enough to cause a human-like parkinsonism in a mouse," Dr. James Surmeier, chair of neuroscience at Northwestern University Feinberg School of Medicine in Chicago, said in a press release.

"Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons," said Dr. Surmeier.

He and his colleagues also demonstrated that gene therapy targeting the substantia nigra boosted the effects of levodopa in their "MCI-Park" mouse model of Parkinson's disease.

They used intersectional genetics to disrupt the function of mitochondrial complex I (MCI) in mouse dopaminergic neurons, they explain in a report in Nature.

This induced a "Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axon," write the authors.

"This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism - which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm," they add.

The researchers also found that treatment with an adeno-associated viral (AAV) vector expressing aromatic-l-amino acid decarboxylase (AADC) protein, which helps convert levodopa to dopamine, boosted the effect of levodopa therapy in the mice.

In a Nature News & Views, Dr. Zak Doric and Dr. Ken Nakamura with the Gladstone Institute of Neurological Disease in San Francisco, say this research provides "an exquisitely detailed description of the progression of neurodegeneration associated with mitochondrial dysfunction, and its impact on movement and neuronal function in the model mice."

"By demonstrating a severe decrease in the function of these dopamine neurons before the loss of the actual neurons, this work also calls into question the widely taught principle that most dopamine neurons are dead by the time the disease symptoms begin. Instead, it supports evidence from post-mortem investigations that many of these neurons in people with symptoms of Parkinson's disease might still be living and salvageable using future disease-modifying therapies," they write.

Dr. Doric and Dr. Nakamura say this research also has implications for approaches in the design of treatments to restore dopamine signaling in people with Parkinson's disease through gene therapy or by replacing the lost cells.

"So far, these approaches have focused mainly on creating dopamine 'pumps' in the striatum, either by transplanting dopamine-producing cells into the brain or by delivering viruses into the striatum that express the molecular machinery needed to make dopamine. The MCI-Park model suggests that restoring dopamine release in the substantia nigra might help to relieve the disease's movement symptoms, too," Dr. Doric and Dr. Nakamura say.

This research did not have commercial funding.

SOURCE: https://go.nature.com/3H8Ua9u and https://go.nature.com/3H89Jy6 Nature, online November 3, 2021.

By Reuters Staff



Posted on 11 November 202116 November 2021