Table 1.
Patient-derived induced pluripotent stem cell-based modeling of Parkinson’s disease
| Gene mutation | Inheritance type | Differentiated cell types | In vitro phenotypes (normalized to normal control / non-isogenic control) | Ref. |
| A53T SNCA | Familial | DA neurons | Not demonstrated | [52] |
| Triplication SNCA | Familial | DA neurons | Elevated levels of SNCA mRNA Increased cellular and secreted α-synuclein protein | [40] |
| Triplication SNCA | Familial | DA neurons | Elevated α-synuclein protein expression Increased expression of oxidative stress-related genes Increased susceptibility to oxidative stress | [53] |
| SNCA (A53T)/triplication SNCA | Familial | Forebrain cortical neurons | Nitrosative stress Accumulation of ERAD substrates ER stress | [58] |
| Triplication SNCA | Familial | Neural precursor cells | High vulnerability to stress Increased ROS production | [59] |
| Triplication SNCA | Familial | Neural precursor cells/DA neurons | Impaired neuronal differentiation and maturation pSer129-aSyn accumulation Increased susceptibility to oxidative stress | [56] |
| LRRK2 (G2019S) | Familial | |||
| SNCA (A53T) | Familial | DA, GABAergic,and glutamatergic neurons | Protein aggregation (thioflavin S and pSer129-aSyn) Axonal neuropathology Altered expression of synaptic transcripts | [57] |
| LRRK2 (G2019S) | Familial | DA neurons | Reduced neurite outgrowth Dysregulated autophagy system Increased cell death in response to neurotoxins Elevated αsynuclein protein level Dysregulation of genes related to DA neurodegeneration | [61] |
| LRRK2 (G2019S) | Familial | Neural stem cells | Increased sensitivity to stress Progressive impairment in nuclear envelope organization Defective self-renewal and neuronal differentiation | [62] |
| PINK1 (Q456X) | Familial | DA and nonDA neurons, and immature cells | Increased vulnerability to stress Dysfunction of mitochondria | [63] |
| LRRK2 (G2019S) | Familial | [63] | ||
| PINK1 (Q456X or R275W) | Familial | DA neurons | Increased neuronal death Degenerated dendrites Impaired AKT signaling | [72] |
| PARK2 (V324A) | Familial | [72] | ||
| LRRK2 (G2019S) and Sporadic | Familial and Sporadic | DA neurons | Increased apoptosis Reduced neurite numbers and complexity Increased autophagic vacuoles | [81] |
| SCNA (A53T) | Familial | DA neurons | Elevated αsynuclein aggregation and Lewy-body-like deposition Induced nitrosative and oxidative stress Increased vulnerability to mitochondrial toxin-induced cell death | [55] |
| SCNA (A53T) | Familial | DA neurons | Decreased αsynuclein tetramers Increased neurotoxicity | [56] |
| PARK2 (exon 2–4 deletion or exon 6, 7 deletion) | Familial | DA neurons | Increased oxidative stress, activated NRF2 pathway Abnormal mitochondrial morphology and turnover. Elevated αsynuclein accumulation | [70] |
| PARK2 (exon 3, 5 deletion or exon 3 deletion) | Familial | DA neurons | Increased oxidative stress Reduced dopamine uptake Enhanced spontaneous dopamine release | [71] |
| PINK1 (c.1366C>T; p.Q456X or c.509T>G; p.V170G) | Familial | DA neurons | Impaired recruitment of Parkin to mitochondria Increased mitochondria copy number PGC1α upregulation | [74] |
| PARK2 (exon 3, 5 deletion or exon 3 deletion) | Familial | DA neurons | Reduced neurite complexity Diminished microtubule stability | [73] |
| PARK2 (R42P, exon 3 deletion, exon 3, 4 deletion, 255A deletion, R275W or R42P) | Familial | DA neurons | Reduced capacity to differentiate into DA neurons Altered mitochondrial volume fraction | [75] |
| LRRK2 (G2019S) and sporadic type | Familial/sporadic | DA neurons | Elevated oxidative stress response Increased sensitivity to stress-induced cell death | [64] |
| LRRK2 (G2019S) and Sporadic PD | Familial/sporadic | DA neurons | Hypermethylation in gene regulatory regions Reduced expression of transcription factors related to disease | [65] |
| GBA1 (RecNcil/+, L444P/+ or N370S/+) and sporadic type | Familial/sporadic | DA neurons | Reduced dopamine storage and uptake Elevated α-synuclein and glucosylceramide levels Defective autophagic and lysosomal machinery Increased basal and induced calcium levels Enhanced vulnerability to ER stress | [77] |
| GBA (N370S/+) and sporadic type | Familial/ sporadic | DA neurons | Elevated αsynuclein levels Reduced dopamine levels Induced MAOB expression Disrupted network activity | [78] |
| GBA1 and sporadic | Familial/ sporadic | DA neurons | Decreased dopamine storage and uptake Elevated αsynuclein levels | [79] |
| SCNA SNP | Sporadic | Neurons | Disease-associated risk variant that regulates SCNA expression | [49] |
| SCNA (A53T) | Familial | DA neurons | Elevated nitrosative stress SNCAA53T or mitochondrial toxins induce S-nitrosylated (SNO)-MEF2C in DA neurons S-nitrosylation of MEF2C reduces PGC1α expression and impairs mitochondrial function | [54] |
ERAD: Endoplasmic-reticulum-associated degradation; MAOB: Monoamine oxidase B; NRF2: Nuclear factor erythroid 2related factor 2; SNP: Single-nucleotide polymorphism; TH: Tyrosine hydroxylase.