Key to Neuron Death in Parkinson’s Disease Found in Aging Mitochondria

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by Magdalena Kegel |

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Researchers may have come a step closer to understanding the cause of Parkinson’s disease, in a study showing how the inability to degrade old mitochondria — the power plants that charge our cells — leads to the death of dopamine neurons.

The findings also explain the role of the LRRK2 gene in Parkinson’s disease. The factor, linked to both hereditary forms and a large proportion of spontaneous cases of the disease, impacts a key step in the breakdown of mitochondria.

Researchers believe that many other conditions can lead to a failure of this key step, which might turn out to be the key event causing Parkinson’s disease.

The study, “Functional Impairment in Miro Degradation and Mitophagy is a Shared Feature in Familial and Sporadic Parkinson’s Disease,” published in the journal Cell Stem Cell, will possibly point researchers toward new techniques to prevent the death of neurons, thereby preventing or treating Parkinson’s disease.

Many researchers have suspected that faulty mitochondria are somehow involved in Parkinson’s, but the research team at Stanford University Medical Center has now shown exactly how this is happening.

“Existing drugs for Parkinson’s largely work by supplying precursors that faltering dopaminergic nerve cells can easily convert to dopamine,” Dr. Xinnan Wang, MD, PhD, and an assistant professor of neurosurgery at Stanford, said in a news release. “But that doesn’t prevent those cells from dying, and once they’ve died you can’t bring them back.”

In the process of producing energy from nutrients, mitochondria become filled with substances that are highly toxic to cells. To prevent those compounds from leaking out and harming the cell, there is usually a highly efficient system for removing old mitochondria.

These cellular components do not float around inside the cell at random, but are attached to a network of fine fibers known as the cytoskeleton. A protein called Miro is used to attach mitochondria to these fibers, and the connection needs to be broken before the worn-out power plant can be transported away for careful disassembly.

The Stanford team discovered that to detach mitochondria, LRRK2 needs to form a complex with Miro. If LRRK2 is mutated or otherwise defective, the attachment is slow to break.

Researchers grew skin cells from five sporadic Parkinson’s patients; six patients with familial Parkinson’s with confirmed LRRK2 mutations, including the most common mutation known as LRRK2G2019S; and five patients with inherited Parkinson’s carrying other mutations. They also included cells from four healthy volunteers to be used as controls.

In cells from healthy people, Miro was degrading at a normal rate, but in all Parkinson’s patients, the breakdown of the protein was severely slowed down. They also noted that this led to a significant delay in the destruction of worn out mitochondria.

They also discovered that cells from Parkinson’s patients were much more sensitive to the effects of free radicals  — oxidant compounds that can damage cells. When researchers boosted the production of such compounds, many more cells derived from patients died than those derived from healthy people. Wang explained that such conditions are often seen in midbrain dopamine neurons.

The efforts of the research team produced more than just evidence of how Parkinson’s nerve cells die. Researchers also showed that by lowering the concentration of Miro in the cells, they could speed up mitochondrial detachment and disassembly and prevent the death of the neurons.

Researchers discovered that lower levels of Miro did not set healthy mitochondria lose, but instead lowered the effort needed to break the link between a mitochondrion and the cytoskeleton. Repeating the experiments with free radicals, the research team noted that far fewer nerve cells died. Lowering Miro in a fruit fly model of Parkinson’s also improved the movement ability of the flies.

Wang and her team believe that LRRK2 can fail to sever the Miro-mitochondrial connection even in the absence of mutations. Such failures could also be caused by other problems in the cell, and so, they think that measurements of Miro could be an early marker, allowing doctors to detect the advent of disease before symptoms occur. And it may turn out that this process is the key event leading to Parkinson’s disease.

“Measuring Miro levels in skin fibroblasts from people at risk of Parkinson’s might someday prove beneficial in getting an accurate, early diagnosis. And medicines that lower Miro levels could prove beneficial in treating the disease,” Wang concluded.

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