Researchers Say They Have Clue to Early-Onset Parkinson Disease

A study published Monday, focusing on patients with Parkinson disease (PD) who developed the nervous system disorder before the age of 50, says these individuals may have been born with disordered brain cells that went undetected for decades.

To perform the study, researchers at Cedars-Sinai Medical Center and UCLA generated special stem cells, known as induced pluripotent stem cells (iPSCs), from cells of 3 patients with young-onset Parkinson disease; the patients were aged 30-39 and had no known familial history of PD or PD mutations.

The process involved taking adult blood cells back to a primitive embryonic state. These iPSCs can then produce any cell type of the human body, all genetically identical to the patient's own cells. The team used the iPSCs to produce dopamine neurons from each patient and then cultured them in a dish and analyzed the neurons' functions.

The researchers detected 2 key abnormalities in the dopamine neurons:

• Accumulation of alpha-synuclein, a protein that occurs in most forms of Parkinson disease
• Malfunctioning lysosomes, cell structures that help the cell to break down and dispose of proteins; in this case, the malfunction could cause alpha-synuclein to build up.

The hypothesis is that dopamine neurons may mishandle alpha-synuclein over a period of 20 or 30 years, causing Parkinson disease symptoms.

The investigators also used their model to test a number of drugs that might reverse the abnormalities. One drug, PEP005, or ingenol mebutate gel, used for basal cell carcinoma, reduced the elevated levels of alpha-synuclein in both the dopamine neurons in the dish and in laboratory mice.

The drug also countered another abnormality they found in the patients' dopamine neurons—elevated levels of an active version of an enzyme called protein kinase C. However, the role of this enzyme version in Parkinson disease is unknown.

In Parkinson, brain neurons that make dopamine, a substance that helps coordinate muscle movement, become impaired or die. The disease is diagnosed in at least 500,000 people in the United States each year, and the incidence is rising. About 10% are aged 21 to 50 years.

Michele Tagliati, MD, director of the Movement Disorders Program, vice chair and professor in the Department of Neurology at Cedars-Sinai, said the team plans to investigate how PEP005 might be delivered to the brain to potentially treat or prevent young-onset Parkinson. The team also plans more research to determine whether the abnormalities the study found in neurons of young-onset Parkinson's patients also exist in other forms of the disease.

Reference

Laperle AH, Sances S, Yucer N, et al. iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates [published online January 27, 2020]. Nat Med. doi: 10.1038/s41591-019-0739-1.