Parkinson's disease (PD) is the most common neurodegenerative movement disorder, for which disease-modifying therapy has not yet been established. It is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in substantia nigra pars compacta (SNpc) and the presence of Lewy bodies, which contain phosphorylated alpha-synuclein (SNCA). However, its pathogenic processes remain elusive.
While most PD cases are sporadic, cellular and animal models of genetic PD have provided us the insights into its pathogenesis. Mutations in leucine-rich repeat kinase-2(LRRK2) are the most common cause of familial PD. In addition, the genome-wide association studies (GWAS) have identified LRRK2 gene as a susceptibity gene for sporadic PD, along with SNCA gene. Although myriads of functions have been proposed for LRRK2, their relevance to the disease remains unclear. Recently, rare variants in the glucocerebrosidase (GBA) gene are also identified as a genetic risk factor for sporadic PD.
A major barrier to the research on PD is inaccessibility of the diseased neurons for study. One potential solution is to derive induced pluripotent stem cells (iPSCs) from patients and differentiate them into mDA neurons affected by disease. Several recent reports have suggested iPSC-derived neural cells from genetic PD patients could recapitulate PD-related phenotypes.
We have established iPSCs from PD patients harboring LRRK2, SNCA and GBA mutations as well as non-diseased individuals, and successfully generated mDA neurons from these iPSCs with 10-30% efficiency. These iPSC-derived mDA neurons will hopefully become cellular models for exploring PD pathomechanisms and platforms for drug development.