Parkinson’s disease has notched up some high profile scalps over the years, including actor Michael J Fox, former crooner Linda Ronstadt and late great pugilist Muhammad Ali.
But the incurable brain disease, which leaves victims with the shakes, rigid limbs and actions slowed to a crawl, cuts a broad, if more muted, swathe through ordinary society. There are 110,000 Australians living with the disease and their average time from diagnosis to death is little more than 12 years.
New research, however, published in the journal Nature Communications and led by neurobiologist Scott Ryan from the University of Guelph in Ontario, Canada, shines light on what goes awry deep inside the brain cells of sufferers, and may open a door to new treatment.
Parkinson’s kills off brain cells that make dopamine, and it’s the lack of this neurotransmitter that unhinges motor control. Hence those miraculous images of the late neurologist Oliver Sacks “waking up” his frozen patients with the dopamine precursor levodopa, a drug that remains in use today but whose effects are often, sadly, short-lived.
Ryan’s team has shown, for the first time, how a protein called alpha-synuclein – alpha-syn for short – contributes to the death of dopamine-making brain cells. The researchers found that in normal cells a lipid called cardiolipin migrates to the outer wall of the mitochondrion, the cell’s powerhouse, where it folds alpha-syn, origami-like, into a non-toxic shape.
Using stem cells from people with Parkinson’s, the researchers then showed that genetic errors produce a mutant alpha-syn that effectively renders cardiolipin cack-handed. It simply can’t wrest the mutant protein into the requisite folded pattern and ultimately, as a result, it wreaks mitochondrial havoc. The mitochondrion undergoes autophagy – literally, it eats itself – and the neuron housing it succumbs thereafter.
Dramatically, the team also showed that mutated alpha-syn is transmitted, virus-like, from neuron to neuron, a process that took just 30 days in mice, and left decimated mitochondria in its wake.
But the researchers also made a discovery that offers hope of a new target for treatment. They raised a type of monoclonal antibody – identical immune cells derived from a single ancestor – against alpha-syn that was able to halt its insidious spread outright.
“Alpha-syn immunotherapy is a promising avenue that warrants further exploration,” the authors write. “Therapeutic approaches that block alpha-syn transmission may have a role as an adjunctive therapy.”
“Currently there are no treatments that stop nerve cells from dying,” says Ryan. “We now have a better understanding of why nerve cells die in Parkinson’s disease and how we might be able to intervene.”
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