Parkinson’s is known to involve a defect in mitochondrial function. The harder a cell has to work, the more energy its mitochondria have to churn out — and the more likely they’ll burn out. Dopaminergic neurons in the substantia nigra are among the body’s hardest-working cells.
Mitochondria spend much of their time attached to a grid of protein “roads” that crisscross cells. Like old cars that can no longer pass a smog test because they can’t stop spewing noxious exhaust fumes, defective mitochondria have to be taken off the road. Our cells have a technique for clearing mitochondrial clunkers: a series of proteins that shuffle them off to the cell’s recycling centers. But first, those proteins have to remove an adaptor molecule called Miro that attaches mitochondria, damaged or healthy, to the grid.
Wang’s group previously identified a mitochondrial-clearance defect in Parkinson’s patients’ cells: Their inability to remove Miro from damaged mitochondria.
In the new study, Wang’s team obtained skin samples from 83 Parkinson’s patients, five asymptomatic close relatives considered to be at heightened risk, 22 patients diagnosed with other movement disorders and 52 healthy control subjects. They extracted fibroblasts — cells that are common in skin tissue — from the samples, cultured them in petri dishes and subjected them to a stressful process that messes up mitochondria. This should result in their clearance, necessarily preceded by removal of Miro molecules tethering them to the grid.
Yet the researchers found the Miro-removal defect in 78 of the 83 Parkinson’s fibroblasts (94%) and in all 5 of the “high-risk” samples, but not in fibroblasts from the control group or other or from patients with other movement-disorders.
Screening small molecules
Next, the investigators screened 6,835,320 small molecules, whose structures reside in a commercially available database, in collaboration with Atomwise Inc. The biotechnology company’s software predicted that 11 of these molecules would bind to Miro in a way that would facilitate its separation from mitochondria and would, in addition, be nontoxic, orally available and able to cross the blood-brain barrier, the study reports.
After feeding these compounds to fruit flies for seven days, the researchers determined that four of them significantly reduced the flies’ Miro levels without toxicity. They tested one compound, which appeared to target Miro most exclusively, on fibroblasts from a patient with sporadic Parkinson’s disease. It substantially improved Miro clearance in these cells after their exposure to mitochondria-damaging stress.
The scientists also fed the compound to three different fruit-fly strains bioengineered to develop Parkinson’s-like climbing difficulty. Administering the compound to those flies throughout their 90-day life spans produced no evident toxicity and prevented dopaminergic neurons’ death in all three strains and, in two, preserved their climbing ability.
Wang said she believes clinical trials of the compound or a close analog are no more than a few years off.
“Our hope,” she said, “is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it.”
Stanford’s Office of Licensing Technology has filed a provisional patent for the use of the study’s lead compound in Parkinson’s disease and other neurodegenerative disorders. Wang has formed a company, CuraX, with the goal of speeding its development.
Researchers at Atomwise and at the Mayo Clinic in Jacksonville, Florida, also contributed to the work.
The study was funded by the National Institutes of Health (grant RO1NS089583), the Klingenstein Fund, the California Institute for Regenerative Medicine, the Archer Fund, Stanford SPARK and a Stanford Parkinson’s Disease Seed Grant from the departments of Neurosurgery and of Pathology.
http://med.stanford.edu/news/all-news/2019/09/scientists-find-potential-diagnostic-tool-treatment.html
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