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Single Cause May Underlie Both Genetic and Sporadic Parkinsonís

Research published in the September 8 edition of Cell Stem Cell finds that a common molecular mechanism may underlie all cases of Parkinson’s disease — both the majority in which the cause is unknown and the rare cases which result from genetic mutations. The discovery paves the way for developing a biomarker for early detection and new therapeutic approaches.

The study builds on recent research into the role of mitochondria in PD. All cells in the body depend on mitochondria to turn nutrients into energy. But over time, mitochondria wear out. Unless they are disposed of promptly, worn-out mitochondria emit toxins that can kill the cell. Dopamine neurons, the type of brain cells lost in PD, may be particularly vulnerable to such toxins.

Researchers led by Xinnan Wang, M.D., Ph.D., at Stanford University focused on a protein called Miro, which holds each mitochondrion to the cell’s internal skeleton. The first step in disposing of worn-out mitochondria is to detach Miro, and free the mitochondrion from this skeleton. To study Miro’s role, they took skin cells from 20 study participants, including healthy people, people with PD of no known cause (sporadic), people with PD who had mutations in the gene LRRK2, and people with inherited PD caused by other genetic mutations. They grew these cells in the laboratory, and used stem cell techniques to create dopamine neurons from them. Then, the scientists analyzed mitochondrial damage and clearance, and the effects of manipulating levels of Miro.

Results

  • In skin cells from healthy people, worn-out mitochondria were freed from the cytoskeleton and sent away for disposal normally.
  • In cells from people with PD, no matter the cause of PD, these processes (mitochondrial detachment and breakdown) were delayed substantially.
  • Normally, the LRRK2 protein plays a role in helping to detach Miro from mitochondria; in cells with mutated LRRK2, this process was slowed.
  • When the researchers deliberately damaged mitochondria, the dopamine neurons derived from people with PD died at a much higher rate than those derived from the cells of healthy people.
  • In cells from people with PD, decreasing the amount of Miro prolonged lives of the cells.
  • In fruit flies with a LRRK2 mutation resulting in movement difficulties similar to PD, lowering Miro levels restored their ability to climb and jump.

What Does It Mean?

Investigating the role of mitochondria has long been a focus of PD research. Earlier studies uncovered ways in which mutations in PINK1, Parkin and α-synuclein, affect mitochondria. The new study adds LRRK2 to the list.

This study also pins down a specific way that LRRK2 proteins play a role in PD — helping to free damaged mitochondria from the cellular skeleton. The study authors also found that this molecular process was disrupted in skin cells from people whose PD did not have a genetic cause. This points to a potential common molecular underpinning of all cases of PD.

If confirmed, a widely applicable diagnostic test might be developed based on this finding. Furthermore, the new study suggests that therapies that lower Miro levels might be effective for PD. This strategy showed promise in cells and in fruit flies. The next step toward potential human therapies is to study the approach in a rodent model of PD.

Reference: Hsieh C-H, Shaltouki A, Gonzolez AE, et al. (2016). Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson’s Disease. Cell Stem Cell 19: 1-16, http://dx.doi.org/10.1016/j.stem.2016.08.002

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Source Date: Oct 11 2016