Research from Cedars-Sinai Medical Center (CA, USA) has demonstrated that cellular malfunctions associated with young-onset Parkinson’s disease could commence long before any outward symptoms. The study, published in Nature Medicine, also revealed that one particular drug could reverse the abnormalities in vitro.
Parkinson’s disease occurs due to a loss of dopamine-producing neurons. In most cases, the cause of neuron failure is unknown, and there is currently no cure.
In this study, researchers focused on investigating the mechanisms underlying young-onset Parkinson’s.
“Young-onset Parkinson’s is especially heartbreaking because it strikes people at the prime of life,” commented Michele Tagliati (Cedars-Sinai), co-author of the study. “This exciting new research provides hope that one day we may be able to detect and take early action to prevent this disease in at-risk individuals.”
In order to carry out the research, the team obtained blood cells from patients with young-onset Parkinson’s disease and took them “back in time” to generate pluripotent stem cells, which they used to produce dopamine neurons.
“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,” commented Clive Svendsen (Cedars-Sinai), senior author of the publication.
Upon analyzing the cultured dopamine neurons, the researchers discovered an accumulation of α-synuclein and malfunctions in lysosomes. Both abnormalities are indicative of Parkinson’s disease.
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“What we are seeing using this new model are the very first signs of young-onset Parkinson’s,” explained Svendsen. “It appears that dopamine neurons in these individuals may continue to mishandle α-synuclein over a period of 20 or 30 years, causing Parkinson’s symptoms to emerge.”
Using their stem cell model, the researchers went on to test a number of drugs that might reverse the observed abnormalities. They discovered that one drug, termed PEP005, which is already approved by the US FDA for treating precancers of the skin, reduced α-synuclein in the dopamine neurons in the dish as well as in laboratory mice.
The drug also countered the raised levels of PKC, another abnormality observed in the patients’ dopamine neurons, although the role of this enzyme in Parkinson’s is currently unknown.
Following on from these results, the team plans to investigate how PEP005 could be delivered to the brain to potentially treat or prevent young-onset Parkinson’s disease. They also intend to carry out further research into the cellular abnormalities found in other forms of the disease.
Sources: Laperle A, Sances S, Yucer N et al. iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates. Nat. Med. doi:10.1038/s41591-019-0739-1 (2020) (Epub ahead of print); www.cedars-sinai.org/newsroom/parkinsons-disease-may-start-before-birth/