Researchers have known for decades that Parkinson’s disease is associated with damage to the nerve cell’s powerhouse, the mitochondria. But whether that mitochondrial damage is a consequence or a cause of the disease has been a matter of debate, according to D. James Surmeier, Ph.D. During the Nov. 9 NIEHS Distinguished Lecture, he presented new research that could put that debate to rest.
The Northwestern University neuroscientist showed that damaging mitochondria in the brains of mice triggers a sequence of events that mimics Parkinson’s disease in humans. By generating insight into how Parkinson’s disease starts and develops, the findings could inspire new ways to stop or slow its progression.
Guohong Cui, M.D., Ph.D., head of the NIEHS In Vivo Neurobiology Group, hosted the event. He noted that Surmeier is recognized for establishing the “selective vulnerability hypothesis” of Parkinson’s disease. The hypothesis describes why only a small subset of the neurons in the brain die in the progressive movement disorder. Because these cells require significant energy, any damage to their mitochondria could accelerate their demise.
An energy crisis
“There are a lot of things that point to mitochondria being a prime player in Parkinson’s disease,” said Surmeier. Age is the number one risk factor for the disease, and mitochondrial activity declines with age. Environmental toxins and genetic mutations that impair mitochondria have been linked to Parkinson’s disease. Alpha synuclein, a protein that forms sticky clumps in the brains of people with the disease, also damages mitochondria.
Surmeier and his team sought to determine whether mitochondrial damage was enough to produce Parkinson’s disease. His laboratory genetically engineered mice to “knock out” a subunit of mitochondrial complex 1 — an enzyme that mitochondria use to produce energy — specifically in dopaminergic neurons. Loss of dopaminergic neurons in the substantia nigra is responsible for the cardinal motor symptoms of Parkinson’s disease. After knocking out the gene for this subunit, they watched to see what happened at the cellular and behavioral levels.
“What we saw was pretty amazing,” said Surmeier. “The cells manifested an astonishing level of plasticity in response to the loss of complex 1 function.” The nerve cells downregulated many genes involved in mitochondrial metabolism and switched to a form of energy production called glycolysis, which does not depend on mitochondria.
Over time, these cells stopped producing dopamine, the chemical messenger that helps to control movement and coordination. As a result, the mice started to exhibit defects in motor learning and fine motor tasks. Later, they had difficulty running, and their posture and gait became impaired.
“This pattern is very much like what we think happens in human Parkinson’s,” said Surmeier.
Because of the human-like staging of the brain pathology and behavior, Surmeier’s group was able to correlate dysfunction in specific brain regions with specific behavioral disability. Contrary to a hypothesis that has dominated thinking for 30 years, they found that loss of dopamine release in the striatum did not lead to Parkinson’s disease symptoms. Rather, dopamine needed to be lost in the rest of the basal ganglia — including the substantia nigra — before mice became parkinsonian.
A potential solution
Surmeier and his colleagues tested a form of gene therapy in the new mouse model of Parkinson’s disease to see whether they could alleviate its motor symptoms. The gene therapy, which uses a gene called AADC, had already been attempted in a human trial.
“The trial was terminated largely because we think the striatum [the region of the brain they delivered it to] was just too big, and you can’t cover it with gene therapy,” said Surmeier. “On the other hand, the substantia nigra is tiny in comparison, so it is one of those places that is relatively easy for a neurosurgeon to cover with a single viral injection.”
Surmeier and his colleagues found that the gene therapy, when delivered to this small group of neurons, increased the ability of the drug levodopa to reverse motor symptoms in mice. “We think that this is potentially a much better target for this therapy in late-stage Parkinson’s disease patients.”
Citation: Gonzalez-Rodriguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt MG, Lopez-Barneo J, Schumacker PT, Surmeier DJ. 2021. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599(7886):650−656.
(Marla Broadfoot, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)