Is Parkinson's Disease a Neurodevelopmental Disorder and Will Brain Organoids Help Us to Understand It?

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The incidence of PD cases increases with age, accordingly classically PD is considered to be an age-associated neurodegenerative disease. In this review, the hypothesis that PD is actually a neurodevelopmental disorder that is compensated for a long time will be discussed. However, patients who suffer from PD typically do not show symptoms early in their lives. This implies that, if the hypothesis that PD has a significant neurodevelopmental component is correct, the developmental defects are compensated for a long time. Furthermore, these developmental defects might not causally lead to the disease but increase the susceptibility for disease onset after a "second hit." In this logic, deregulated developmental processes might represent the "first hit." Even a minor developmental defect could lead to a reduced compensatory capacity or reduced fault tolerance of the entire system. In such a case of an already imbalanced system one or more additional hits could perturb the entire system sufficiently to bring it out of balance and lead to the pathology and symptoms which we classify as PD. However, if the developmental hypothesis and the "multiple hit" hypothesis are correct, an early diagnosis of these developmental defects might allow the start of a therapy for at-risk individuals before disease pathology becomes severe and before symptoms occur. Modern stem cell technologies, including the generation of personalized brain organoids, might play an important role in these strategies.