Using induced pluripotent stem cells for modeling Parkinson’s disease

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.

Table 2 Induced pluripotent stem cell-derived astrocytes in Parkinson’s disease modeling

Cell lines	Differentiated types	Phenotype demonstrated	Ref.
Bone marrow 2-3(BM2-3) hiPSCs	Astrocytes/DA neurons coculture system	Elevated DA neuron identities Stablization of mitochondrial function Downregulation of mitoROS Increased mitochondrial length (normalized to non-co-culture DA neurons)	[88]
iPSCs and ESCs	Astrocytes/DA neurons coculture system	Non-activated astrocytes co-culture system improved DA neurons survival Non-activated astrocytes co-culture system increased DA neurons neurite lengths (normalized to inflammatory-activated astrocytes coculture system)	[89]
LRRK2 mutant and normal iPSCs	PD Astrocytes/normal DA neurons coculture system	Non-cell-autonomous damage is triggered by impaired autophagy in PD astrocytes Dysfunctional PD astrocytes accumulate and transfer α-synuclein to healthy DA neurons CMA activator drug prevents α-synuclein accumulation and neurodegeneration (normalized to the single culture system)	[90]

iPSCs: Induced pluripotent stem cells; ESCs: Embryonic stem cells; hiPSCs: Human induced pluripotent stem cells; PD: Parkinson’s disease; DA: Dopaminergic.

Table 3 Pluripotent stem cell-based genome-editing Parkinson’s disease models

Gene mutation	Editing system	Cell line	Phenotype demonstrated	Application	Ref.
SNCA A30P	CRISPR/CAS 9	hiPSC	Not demonstrated	Locus mutation	[48]
LRRK2 G2019S	ZFN	hiPSC	Not demonstrated	Gene correction	[95]
LRRK2 G2019S	CRISPR/CAS 9	hiPSC	Synaptic defect, fraction of TH+/S129P-αS+ neurons was significantly reduced	Locus mutation	[48]
SNCA E46K	ZFN	hESC	Not demonstrated	Locus mutation	[53]
SNCA A53T	ZFN	hiPSC	Not demonstrated	Gene correction	[52]
SNCA A30P/A53T	CRISPR/CAS 9	hiPSC	Not demonstrated	Locus mutation	[98]
SNCA (rs356165 A/G)	CRISPR/CAS 9	hiPSC	Not demonstrated	Locus mutation	[49]
LRRK2 G2019S	ZFN	hiPSC	Basic phenotypes: autophagy defects, synaptic defects, increased apoptosis, accumulation of τ and α-synuclein. Phenotypes were alleviated after genetic correction	Gene correction	[94]

hiPSC: Human induced pluripotent stem cell.