SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Abstract

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain.

The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy

“…By comparison, disease-specific iPSCs provide new prospects for disease-related R&D by enabling screening for genes and disease processes potentially modifiable by drugs identified through in vitro screening. Consequently, iPSCs have been successfully derived from patients with NDv disorders including schizophrenia [3][4][5][6][7][8][9][10][11], Down's syndrome [12][13][14][15][16][17][18][19][20][21], autism spectrum disorders (ASDs) including fragile X, Rett and Timothy syndromes [22][23][24][25][26][27][28][29][30][31][32][33][34][35], and epilepsy [36][37][38][39], as well as NDg disorders such as Alzheimer's disease [40][41][42][43][44][45][46][47][48], Parkinson's disease [49][50][51][52]…”

Therapeutic Application of Stem Cell Technology toward the Treatment of Parkinson’s Disease

“…In the case of Pd, although "sporadic" Pd patients are more common, approximately 5-10% of Pd patients have a familial etiology, which shows an autosomal recessive or dominant Mendelian inheritance. Recently, several groups generated iPSc lines from sporadic Pd patients 25,26) and familial Pd patients with mutations in α-synuclein (SNcA), 27,28) phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1 (PINK1), 29) leucinerich repeat kinase 2 (lRRK2) 30,31) or parkin. 32,33) Interestingly, these patient-derived iPScs have the potential to differentiate into dA neurons, the same as control iPScs.…”

Systemic and Cell-Type Specific Profiling of Molecular Changes in Parkinson`s Disease

“…iPSCs have been developed and the derived dopamine neruons were characterized for α-synuclein triplication 88 , LRRK2 GS mutation 89 , PINK1 deletion 63 , and parkin mutation 90 . For autosomal dominant PD alleles, synuclein and LRRK2, human dopamine neurons exhibit elevated levels of α-synuclein with increased signs of oxidative stress with some induction of oxidative stress-response genes.…”