Mitochondrial Mishaps Linked to Parkinsons
A recent study from Stanford University suggests that defective mitochondrial clearance may provide the crucial link between genetically and sporadically caused Parkinson’s cases. The researchers have shown that mutations in different genes related to mitochondrial clearance among individuals may cause different ‘types’ of Parkinson’s disease. According to Xinna Wang and her colleagues at Stanford, the Miro protein connects these outlying cases.
Parkinson’s disease is a neurological disorder that affects the motor system. The disorder begins with tremors and eventually leads to stiffness and weakness of muscles, making day-to-day tasks increasingly laborious. At the cellular level, it is caused by the death of neurons that release the neurotransmitter dopamine to the brain region involved in motor function. There is evidence that genetic mutations in specific genes, namely LRRK2, PINK1 and Parkin, are the cause for this decrease in dopamine releasing neurons in many Parkinson’s disease cases.
While 15% of Parkinson’s cases are genetic, the specific functions of these mutated genes are unclear. Prior to Wang’s research, the Parkin and PINK1 mutations were possibly linked to the accumulation of certain proteins called alpha-synuclein, whereas the function of the gene LRRK2 was largely unknown. Moreover, these genetic cases of Parkinson’s were considered completely unconnected in terms of cellular malfunctioning. However, Wang and her colleagues have now found that the mitochondria in LRRK2 related Parkinson’s disease exhibits similarities to the mitochondria in the PINK1 and Parkin cases.
Additionally, other unexplained cases of Parkinson’s disease may also be explained by the new mechanism. “Here’s the best evidence yet that even those forms are some sort of mitochondriopathy,” explains Thomas Schwarz, Wang’s postdoctoral advisor at Harvard University. “Seeing those completely disparate, unrelated spontaneous cases—linked up to this question of how are mitochondria cleared and how is their movement controlled—is absolutely fascinating.”
Mitochondria are fastened onto parts of the cell by a protein called Miro. When the mitochondria age and need to be replaced, Miro loosens and allows for the degradation of the mitochondria and the release of this waste from the cell. However, the neurons carrying the mutations associated with Parkinson’s disease have trouble clearing aged mitochondria. This delay also results in the release of toxic free radicals from the damaged mitochondria that may kill the neuron.
Both Wang and Schwarz have theories to explain why mitochondrial clearance delay in these dopamine-releasing neurons leads to cell death. Wang believes the neurons carrying dopamine are acutely energy-dependent and vulnerable to stress, such that even a minor mishap in energy production might lead to death.
Schwarz, on the other hand, believes these neurons are affected because of the magnitude of mitochondrial regulation these neurons require. “That’s just a staggering burden for the cell to carry,” says Schwarz. “That’s why even a minor slowing or defect in the way the mitochondria are cleared out, or damaged proteins are dealt with, winds up being a major crisis for a cell that has 4.5 meters of axon, compared to a liver cell or even your average neuron elsewhere in the brain.”
The mechanism that impairs mitochondrial clearance in the PINK1/Parkin mutants seems to function alongside the mechanism for the LRRK2 mutation. The most exciting aspect of Wang’s discovery is the possibility of reversing Parkinson’s through this shared protein impairment. By reducing Miro protein expression in these cells, the group was able to reverse neurodegeneration in the mutated cells.
Although the simple reduction in the Miro protein levels served to correct the mitochondrial problems, Wang says this “doesn’t necessarily mean that in humans it is the cause [of Parkinson’s], but suggests it is a possibility—[and] suggests a future direction to look in human patients and see if lowering this protein has any therapeutic benefits.”
Parkinson’s affects 10 million people worldwide, with 60,000 Americans diagnosed each year. The reversal of such a debilitating disease is not a small task, and additional studies will be required to recapitulate and advance Wang’s discovery. Other forms of Parkinson’s disease will need to be inextricably linked to the Miro protein to ensure the neurodegenerative effects can be reversed in Parkinson’s cases other than the LRRK2 mutation. Furthermore, animal studies featuring more complex models, such as mice, will be an important step to launching clinical trials.
Hsieh et al., Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic
Parkinson’s Disease, Cell Stem Cell (2016), http://dx.doi.org/10.1016/j.stem.2016.08.002