Investigators at Northwestern University’s Feinberg School of Medicine have used a new mouse model of Parkinson’s disease (PD) to confirm a causal role for mitochondrial dysfunction in Parkinson’s disease.

More surprisingly, the same model has called into question previously uncontroversial notions about the motor features that are PD’s most conspicuous feature.

“For as long as I’ve been in the field, we’ve thought that when dopamine release in the striatum failed, that’s when you became parkinsonian,” D. James Surmeier explained in an interview on the University’s website.

But “when we saw, very early on, loss of striatal dopamine release, the mice were not parkinsonian at all.”

Surmeier is professor and chair of the physiology department at Feinberg, and the corresponding author of the paper reporting the findings, which appeared in the Nov. 3, 2021, issue of Nature.

Parkinson’s disease is the second most common neurodegenerative disorder, and it is a multifactorial disease that involves many parts of the brain, and can include cognitive and psychiatric symptoms.

But its core motor symptoms are caused by the degeneration of dopaminergic neurons in the substantia nigra.

The substantia nigra is part of the basal ganglia, a part of the brain that controls voluntary movement. In layperson’s terms, the role of the substantia nigra is to help us “do the right thing in the right circumstance to promote our survival… Moving in a way that achieves our goals and avoids punishment," Surmeier said. It also helps automate behavior based on experience.

The substantia nigra projects widely throughout the brain, and its neurons make contact with many other downstream cells.

For those reasons, substantia nigra neurons have high energy demands even by the gluttonous general standards of the brain. “These neurons have a phenotype that puts their mitochondria” – which produce the cellular energy source ATP – “under stress all of the time,” Surmeier said.

“We know that mitochondrial dysfunction is critical to the beginnings of the disease,” and mutations in mitochondrial genes underlie several forms of early-onset familial PD.

But whether mitochondrial damage was truly a driver of disease remained controversial in the scientific community.

Animal models of PD have most often used the toxin MPTP to kill neurons in the substantia nigra. But while the MPTP model reproduced many of the symptoms of PD, both at the behavioral and the cellular level, potential therapies discovered with the approach “failed time and time again” in the clinic, he said. “That model, even though it implicated mitochondria, was not translating.”

Furthermore, in previous experiments, knockout animals missing a protein important for function of the mitochondrial complex 1 (MC1) did not develop PD-like symptoms.

In the work now published in Nature, Surmeier and his team engineered mice to lack another, more critical part of MC1.

The protein the researchers focused on turns over very slowly. And “this turns out to be critical to the outcome of the experiment, because it gave cells time to adapt,” Surmeier said.

The team showed that neurons in the knockout animals switched to glycolysis, which does not take place in the mitochondria, for energy production. The cells were able to survive on that alternate energy.

But their axons became dysfunctional consistent with the idea that mitochondrial dysfunction is a driver of PD, not just a marker.

Surmeier stressed that the work is “not a demonstration that all forms of Parkinsonism are caused through this mechanism.” The protein α-synuclein, which misfolds, aggregates and propagates from cell to cell, plays an important role in the disease as well.

An unexpected translational opportunity

While the findings confirm that mitochondrial-targeting therapies have clinical promise, the work’s most direct translational impact may lie elsewhere.

Dopaminergic substantia nigra neurons are different from most neurons in the brain because they release transmitters not just from their axons, which project to the striatum, but also from their dendrites and cell body, which lie in the substantia nigra itself.

“They communicate with other neurons not just where their axon goes, but also where their cell body sits,” Surmeier said.

Because disease progresses slowly in the model developed by Surmeier and his colleagues, there is a point where axons are no longer releasing dopamine, but the cell bodies and dendrites still are.

And at that point, though the animals had subtle fine motor deficits, if you put them on the floor and let them run around, you couldn’t tell them from normal mice,” he said. “It makes clear that dopamine is acting in other parts of the basal ganglia than just the striatum.”

That, in turn, could breathe new life into gene therapy for PD.

The standard of care for PD patients is the dopamine precursor L-dopa, which is processed into dopamine by the enzyme aromatic acid decarboxylase.

L-dopa is effective at alleviating motor symptoms, but as the disease progresses, its dose needs to be increased to a point where its side effects become intolerable.

A previous clinical trial has attempted to deliver aromatic acid decarboxylase to the striatum, but “had to be terminated because there were complications of trying to get so much enzyme into the striatum,” which is a very large structure.

The substantia nigra is much smaller than the striatum, and so gene therapy here has a better chance of being successful.

And data from the previous trial suggest the approach should be safe. “All we’re essentially doing is targeting it to a slightly different area of the brain,” he said.