Some cases of young-onset Parkinson disease (YOPD) are known to be associated with genetic mutations; however, the majority are not. Although various pathological markers for YOPD have been identified thus far, research is still underway in determining a further means to confirm a diagnosis. A recent study using patient-derived induced pluripotent stem cells found that there is a distinct genetic signature for YOPD even in cells from those who have no known PD-related mutations, according to results published in Nature Medicine.

The researchers collected blood cells from 3 patients with YOPD who were aged 30 to 39 years. The patients had no known family history of PD or any Parkinson mutations. Cells were also generated from a control group. The researchers induced differentiation of these cells into midbrain dopaminergic cultures and analyzed them for accumulation of α-synuclein, a protein that has been tied to the origin and progression of PD. They determined that α-synuclein was expressed differently in YOPD cultures. The findings indicated a YOPD phenotype of transcription-independent α-synuclein accumulation. Aside from this increased in α-synuclein, there were also increased levels of phosphorylated protein kinase Cα present in the samples and reduced lysosomal membrane proteins among the YOPD cultures. The researchers repeated the study with cells from an additional 9 patients with YOPD and 7 control individuals. The molecular signature they isolated was shown to correctly identify PD in 21 of 22 patients.

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Overall, the study revealed that there is a specific genetic signature for YOPD in patients with no family history of PD or disease-related mutations. Because PD is thought to be caused by a combination of genetic and environmental factors that are not completely understood, this investigation provides insight into the molecular pathology of the disease. The molecular markers identified for YOPD, increased α-synuclein and protein kinase Cα levels, encompass a finding the researchers hope to further validate in future studies. They note that the identification of these markers could serve as the basis for important diagnostic and therapeutic pathways, which might allow for earlier detection of the disease before onset of symptoms.

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Laperle, A.H., 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. 2020;26(2):289-299