Parkinson's discovery could yield new treatment strategy for young onset patients

The protein alpha-synuclein is a major culprit in Parkinson’s disease because it misfolds and clumps up in the brain, causing cells that produce needed dopamine to die. In up to 10% of Parkinson’s patients, the symptoms strike before age 50, and researchers at Cedars-Sinai now believe they’ve found a key mechanism behind this young onset form of the disease.

Using induced pluripotent stem cells (iPSCs) from patients with young onset Parkinson’s, the team discovered that dopamine-producing neurons mishandle alpha-synuclein for decades before symptoms appear, possibly starting before birth. They even found a drug that reduced levels of alpha-synuclein in dopamine neurons, both in lab dishes and in mouse models. They reported the discovery in the journal Nature Medicine.

The researchers took blood cells from Parkinson’s patients and reprogrammed them into iPSCs, essentially setting them back to their embryonic state. Then they used them to produce dopamine neurons.

They discovered that the primitive neurons they created had malfunctioning lysosomes, which are structures inside of cells that normally break down proteins and discard them. That could be why the cells were accumulating alpha-synuclein, they hypothesized.

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The Cedars-Sinai team then used their iPSC models to screen several drugs until they hit on one that could reverse the lysosome abnormality. The drug is Picato (PEP005), a gel developed by Leo Pharma that’s used to treat precancerous skin lesions. Interestingly, the gel also corrected another abnormality the researchers found, which was an activated version of protein kinase C, though it’s unclear whether that protein is related to Parkinson’s.

Combating the buildup of alpha-synuclein is a major focus of Parkinson’s research. Among the biotech companies that are developing drugs designed to combat alpha-synuclein clumping are Enterin, Voyager and Modag, the latter of which came out of stealth mode last year with $14 million in series A funding.

Several academic groups are investigating the link between the gut microbiome and alpha-synuclein buildup in Parkinson’s. Johns Hopkins University researchers published a study last year showing that misfolded alpha-synuclein can travel from the gut to the brain in mice. And earlier this month, U.K. researchers discovered that in roundworm models of the disease, the bacterium Bacillus subtilis changes fat metabolism in cells in a way that prevents the clumping of alpha-synuclein.

The next step for the Cedars-Sinai team is to determine whether the abnormalities they found in cells derived from young onset Parkinson’s patients characterize any other forms of the disease. They also plan to develop formulations of PEP005 that could be delivered to the brain to treat or prevent the disease.

The research “provides hope that one day we may be able to detect and take early action to prevent this disease in at-risk individuals,” said co-author Michele Tagliati, M.D., professor and director of the Movement Disorders Program at Cedars-Sinai, in a statement.