Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Abstract

Parkinson's disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson's genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson's patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson's disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson's patients may guide future personalized drug screens in preclinical research.

GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson’s disease

“…Our data show that pretreatment with the flavonoid, GA, significantly improves survival, mobility defects, and dopaminergic neuron loss against PQ-induced neurotoxicity in Drosophila . Another group reported the involvement of GA in promoting neuritogenesis in PC12 cells and neurite alterations have been observed in PD patients 28 , 48 . On the other hand, the structurally related GardeninB (GB) failed to protect against PQ-induced neurotoxicity, which could potentially be attributed to the lower number of methoxy groups attached to the parent flavone skeleton.…”

The Endoplasmic Reticulum Stress/Unfolded Protein Response and Their Contributions to Parkinson’s Disease Physiopathology

“…Even if it is still debated, high-temperature requirement A2 (HTRA2/Omi/PARK13) is often considered as a PD risk factor [ 179 , 180 ]. HTRA2 is a serine protease with strong homology to the Escherichia coli HTRA2, that are important to bacterial survival at high temperatures.…”

GardeninA confers neuroprotection against environmental toxin in aDrosophilamodel of Parkinson’s disease

“…Our data show that pretreatment with the flavonoid, GA, significantly improves survival, mobility defects, and dopaminergic neuron loss against PQ-induced neurotoxicity in Drosophila. Another group reported the involvement of GA in promoting neuritogenesis in PC12 cells and neurite alterations have been observed in PD patients 29,48 . A recent study revealed significant antidepressant actions of GA, thereby suggesting neuropharmacological effects in mice 49 .…”