"Our technique gave us a window back in time to see how well the dopamine neurons might have functioned from the very start of a patient’s life,” said Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine at Cedars-Sinai. He was the study’s senior author.

The researchers detected two key abnormalities in the dopamine neurons in the dish:

Accumulation of a protein called alpha-synuclein, which occurs in most forms of Parkinson’s disease.

Malfunctioning lysosomes, cell structures that act as "trash cans" for the cell to break down and dispose of proteins. This malfunction could cause alpha-synuclein to build up.

"What we are seeing using this new model are the very first signs of young-onset Parkinson’s," said Svendsen. "It appears that dopamine neurons in these individuals may continue to mishandle alpha-synuclein over a period of 20 or 30 years, causing Parkinson’s symptoms to emerge."

The investigators also used their iPSC model to test a number of drugs that might reverse the abnormalities they had observed. They found that that one drug, PEP005, which is already approved by the Food and Drug Administration for treating precancers of the skin, 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 — although the role of this enzyme version in Parkinson's is not clear.

For the next steps, Tagliati said the team plans to investigate how PEP005, currently available in gel form, might be delivered to the brain to potentially treat or prevent young-onset Parkinson’s. 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 Parkinson’s.

"This research is an outstanding example of how physicians and investigators from different disciplines join forces to produce translational science with the potential to help patients," said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. "This important work is made possible by the dual leadership of Cedars-Sinai as both a distinguished academic institution and an outstanding hospital."

The study's co-first authors were postdoctoral fellow Alexander Laperle, PhD, and project scientists Samuel Sances, PhD, and Nur Yucer, PhD, all from Svendsen’s laboratory. Besides the Regenerative Medicine Institute and Neurology, the study involved the Department of Biomedical Sciences, Center for Bioinformatics and Functional Genomics, Smidt Heart Institute, Samuel Oschin Comprehensive Cancer Institute and the Research Division of Immunology at Cedars-Sinai, along with UCLA.

Funding: This work was supported by the Joseph Drown Foundation, the Cedars-Sinai Board of Governors Regenerative Medicine Institute, the National Institutes of Health under award number 5UG3NS105703-02, the Widjaja Family Foundation and the Advanced Clinical Biosystems Research Institute at Cedars-Sinai.

Competing interests: Intellectual property protection is pending for disease modeling, diagnostics and drug screening for molecular signatures of early-onset sporadic Parkinson’s disease, and the use of PEP005 for Parkinson’s disease.

DOI: 10.1038/s41591-019-0739-1."iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates."

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