Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by progressive degeneration of SNc dopaminergic neurons leading to clinical parkinsonian symptoms (bradykinesia, resting tremors, muscular rigidity, and postural instability). Although the majority of patients do not have a clear family history of PD (sporadic PD), genetic studies have identified several genes which cause familial forms of PD including α-synuclein, LRRK2, VPS35, ATP13A2, PINK1, parkin, DJ-1 and GBA1. Furthermore, brains of sporadic and familial PD patients also show formation of Lewy bodies consisting of α-synuclein deposits, suggesting that α-synuclein accumulation and toxicity is a key player in PD pathogenesis. Our lab studies the function of multiple PD genes and converging cellular mechanisms both upstream and downstream of α-synuclein toxicity in order to ultimately identify new therapeutic targets for familial and sporadic PD. Using patient-derived induced pluripotent stem cells (iPSCs) differentiated into dopaminergic neurons, we have found that 1) upstream dysfunction in multiple PD genes including ATP13A2, parkin, DJ-1 and GBA1 leads to α-synuclein accumulation and defects in both endolysosomal and mitochondrial pathways; and 2) downstream α-synuclein accumulation additionally results in lysosomal dysfunction by disrupting trafficking of multiple lysosomal enzymes including β-glucocerebrosidase (GC) that is coded by GBA1. We and others have found that the function of wild-type GC is also decreased in idiopathic/sporadic PD, suggesting the importance of this pathways in both genetic and sporadic forms of disease. We are now identifying novel compounds which efficiently target and activate GC in order to reduce α-synuclein toxicity and provide neuroprotection in Parkinson’s disease.
|Effective start/end date||2/1/18 → 2/1/21|
- Wanxiang America Corporation (Agmt 05/10/18)
Induced Pluripotent Stem Cells