Parkinson’s disease, the second-leading neurodegenerative disorder after Alzheimer’s disease, affects one in every 60-70 Americans age 65 or older. While the vast majority of all cases are sporadic, 5-10 percent are familial: Some factor predisposing for the condition is handed down from parents to children.
The most frequent genetic mutations responsible for familial Parkinson’s occur at various points along a gene coding for a protein called LRRK2. Several such mutations are known, but genetic tests reveal that the mutation known as LRRK2G2019S is the most prevalent, turning up in 1 in 20 of familial cases and 1 in every 50 apparently sporadic cases among Caucasians. Curiously, LRRK2G2019S shows up in 40 percent of familial Parkinson’s cases and 13 percent of sporadic cases among Ashkenazi Jews ….
Until now, no one could account for LRRK2’s connection to Parkinson’s. In extensive experiments with cells cultured from Parkinson’s patients and healthy subjects, Stanford neuroscientist Xinnan Wang, MD, PhD, and her colleagues have cleared up that mystery.
And that’s not all. The study reveals an underlying pathological mechanism that not only explains what’s going on with the LRRK2 mutation, but may enlighten researchers about Parkinson’s’ sporadic forms, too.
It’s known that Parkinson’s is precipitated by a massive die-off of a set of hardworking, energy-gluttonous midbrain nerve cells whose nonstop activity fine-tunes our voluntary movements. The these nerve cells’ vulnerability may spring directly from their constant energy ocnsumption, which over the decades probably increases the rate at which their intracellular power supplies (called mitochondria) burn out, stop supplying energy and start spewing out noxious pollutants instead.
Cells deal with bad mitochondria by having them carting off to intracellular garbage disposals for decommission. But this can’t happen, Wang and her associates observed, until those faulty mitochondria are sawed loose from the so-called cytoskeleton — a network of molecular filaments and tubules that spans and shapes most of our cells. And for this to take place, the scientists learned, LRRK2 — the very protein encoded by the gene tied to heritable Parkinson’s disease — has to form a stable complex with a little molecular anchor that hooks mitochondria to the cytoskeleton.
The really amazing finding in this study was that, in cells from every form of Parkinson’s examined — from patients with sporadic cases and familial cases alike — but in none of the cells from healthy control subjects, the researchers observed a substantial delay in cells’ ability to pry loose damaged, dysfunctional mitochondria. Implication: Even when LRRK2 itself isn’t rendered defective by a mutation, anything impairing this protein’s ability to complex with faulty mitochondria’s molecular anchor produces the same result — a hugely stressed nerve cell that’s much more susceptible to biting the dust.
This gives neuroscientists and drug developers an entirely new target to shoot at. In the study, pharmacological actions that made for easier faulty-mitochondria severing prevented vulnerable nerve cells from dying. That could be big.
Previously: Stanford study points to precisely positioned deep-brain-stimulation devices for Parkinson’s, Stanford conducts first U.S. implantation of deep-brain-stimulation device that monitors, records brain activity and Revealed: The likely role of Parkinson’s protein in the healthy brain
Photo by Peter Jackson