LAUSR

About 10% of Parkinson’s disease (PD) patients are diagnosed between ages 21 and 45 years, which is known as young-onset PD (YOPD). Because about 80% of YOPD patients do not have known PD mutations or family history and the disease strikes people in the prime of life, understanding its pathogenesis is urgently needed to pave the way to discovery of novel therapeutic agents. Because of the difficulty of accessing patient dopamine neurons and poor animal models of YOPD, reprogramming patient-derived somatic cells into dopamine neurons represents an ideal model for PD research. In a recent issue of Nature Medicine, Svendsen and colleagues revealed a molecular signature of YOPD and identified a drug candidate for treating it by induced pluripotent stem cell (iPSC) modeling technology. Specifically, the authors first generated iPSCs from blood mononuclear cells of YOPD patients and subsequently induced them to differentiate into midbrain dopaminergic (mDA) cultures. By using a series of advanced technologies including RNA-seq and proteomics analyses, they identified 2 key abnormal characteristics in YOPD mDA. These are accumulation of α-synuclein independent of transcription and malfunction of lysosomes (with reduced lysosomal proteins and hydrolase activity). They further showed that lysosomal deficiency may cause the accumulation of α-synuclein because its degradation was not mediated by the proteasome in YOPD mDA cells. Notably, YOPD patients do not have known PD mutations but end up with common molecular markers of lysosomal dysfunction, indicating that there might be uncharacterized genetic contributions to their disease. Next, they tested the effects of several drugs on restoring abnormal characteristics in YOPD mDA neurons and found that PEP005, an Food and Drug Administration–approved drug for treating skin precancers, effectively degraded α-synuclein both in vitro and in vivo. Therefore, PEP005 has the potential to develop into a novel drug candidate for treating YOPD. Although elevated phosphorylated protein kinase Cα (p-PKCα), a member of the protein kinase family that phosphorylates hydroxyl groups of many proteins, was also found in YOPD mDA, the p-PKCα contents were not validated in postmortem PD tissues, and the function of p-PKCα in PD is unclear. Overall, iPSC-derived mDA cultures are a unique model for YOPD research because this model preserved the precise patient genome and mimicked key essential disease pathological processes. This interesting study revealed the unique molecular signature in iPSC-derived mDA cultures that may be used for early YOPD diagnostics. Importantly, this work provides a screening platform for discovery of novel therapeutic drugs for YOPD.