A study by researchers at Cedars-Sinai research has found that people who develop Parkinson’s disease before the age of 50 may have been born with dysfunctional brain cells that allow gradual accumulation of the α-synuclein protein that forms abnormal deposits in patients with the disease, and dysregulated lysosomal proteins that would normally play a role in clearing abnormal proteins from cells. The research, reported in Nature Medicine, also identified a drug that could help to correct disease processes, and highlighted a molecular signature that might be used to identify early Parkinson’s disease in individuals before symptoms develop.

“Young-onset Parkinson’s is especially heartbreaking because it strikes people at the prime of life,” said co-author Michele Tagliati, MD, director of the Movement Disorders Program, vice chair and professor in the department of neurology at Cedars-Sinai. “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.” Tagliati and colleagues reported on their findings in a paper titled, “iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates.”

Parkinson’s disease is characterized by the death of brain neurons that make dopamine, which normally helps to coordinate muscle movement. Hallmarks of the disease include the formation of Lewy bodies in nerve cells, which contain abnormal aggregates of α-synuclein protein. Progressive symptoms of Parkinson’s disease include slowness of movement, rigid muscles, tremors, and loss of balance. In most cases, the exact cause of neuron failure is unclear, and there is no known cure. At least 500,000 people in the United States are diagnosed with Parkinson’s disease each year, and the incidence is rising. Although most patients are 60 or older when they are diagnosed, about 10% are between 21 and 50 years old. About 80% of these patients have no familial history of disease or genetic mutations that are known to be linked with the disease. “Young-onset Parkinson’s disease (YOPD), defined by onset at < 50 years, accounts for approximately 10% of all Parkinson’s disease cases and, while some cases are associated with known genetic mutations, most are not,” the authors wrote.

Studying Parkinson’s disease is difficult as patients’ dopamine neurons are inaccessible, and animal models aren’t ideal, they continued. One option is to reprogram other types of patient-derived cells into induced pluripotent stem cells (iPSCs), and then differentiate these iPSCs into dopamine neurons. This approach would also effectively take the cells back to a primitive, embryonic state, and generate neurons that are free of any epigenetic control mechanisms that might impact on gene function. “As reprogramming removes most of the epigenetic changes, disease-specific phenotypes originate from the patient’s genetic composition and represent the very earliest stages of the disease process.”

To perform their study, the research team generated iPSCs from peripheral blood mononuclear cells taken from YOPD patients, and differentiated the cells into midbrain dopaminergic (mDA) neuron cells in laboratory culture. “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 senior author Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor of biomedical sciences and medicine at Cedars-Sinai.

Studying these lab-grown neurons the researchers found that they accumulated α-synuclein protein, and exhibited malfunctioning lysosomes, cell structures that act as “trash cans” for the cell to break down and dispose of proteins. This lysosomal malfunction could feasibly cause α-synuclein to accumulate and form aggregates. “These results suggest that increased α-synuclein and lysosomal deficiencies precede accumulation of oxidized dopamine, providing further evidence of dysfunctional lysosomal degradation as the putative cause of α-synuclein accumulation in YOPD mDA cultures,” the authors wrote. Svendsen commented, “What we are seeing using this new model are the very first signs of young-onset Parkinson’s. 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 used their iPSC model to test a number of drugs that might reverse the abnormalities they had observed. They found that one drug, PEP005, which is already approved by the FDA as a topical treatment for actinic keratosis (skin precancers), reduced the elevated levels of α-synuclein in both the dopamine neurons in the dish and in live laboratory mice. The drug also countered elevated levels of phosphorylated protein kinase C (PKC), another anomaly observed in the cultured iPSC-derived dopamine neurons. “Investigating the mechanism of action of PEP005 revealed increased levels of p-PKCα that were specific to the YOPD mDA cultures,” the scientists wrote. The role of this enzyme version in Parkinson’s disease isn’t yet clear.

“We hypothesize that an inability to degrade α-synuclein over many years leads to accumulation of insoluble α-synuclein in dopaminergic neurons, cellular death, and Lewy body formation,” they commented. “Our results support the findings of studies that indicate lysosome dysfunction as a major contributor to PD. While the patients with YOPD did not carry known lysosomal risk variants or display altered lysosomal gene transcription at the pathway level, lysosomal proteins and hydrolase activity were significantly reduced, suggesting that altered lysosomal protein biogenesis and stability may contribute to YOPD-specific accumulation of α-synyclein.”

Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, right, and Nur Yucer, PhD, a project scientist, discuss a microscope image of dopamine neurons. [Photo by Cedars-Sinai]

Tagliati and colleagues suggested that the phorbol ester drug PEP005 represents a “very attractive candidate” as a potential therapeutic agent. The team plans to investigate how the drug 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 identified in neurons of young-onset Parkinson’s patients also exist in other forms of Parkinson’s.

Importantly, their findings could be used to help diagnose Parkinson’s disease in young people. “The combination of accumulation of α-synuclein, dysregulation of lysosomal biogenesis and function, and increases in p-PKCα was a highly predictive phenotype in our model of YOPD, and thus represents a new diagnostic tool for clinicians,” they stated. “Our p-PKCα findings in iPSC-derived mDA cultures provide an exciting molecular marker for PD, which we plan to further validate in postmortem PD.”

The work could also enable the development of a screening platform for new drugs that act on the observed mechanisms of YOPD, they suggested. “For example, we have identified drugs that target this signature and reduce intracellular α-synuclein levels in control and disease-derived cells. These phorbol ester drugs, in particular PEP005, may treat the underlying cause of YOPD and could uncover shared principles with other neurodegenerative disorders. A definitive diagnosis could initiate phorbol ester-based drug treatment early in disease to reduce α-synuclein accumulation and increase TH [tyrosine hydroxylase] levels, both of which could have potentially stabilizing effects to delay disease onset and slow progression.”

“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.”

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