Table 1.

Neuronal phenotypes of patient iPSCs of neurodegenerative diseases and therapeutic options

Model	Genetic mutation	Neuronal phenotypes	Therapeutic options
Alzheimer’s disease	PS1 (A246E) and PS2 (N141I)	Increased Aβ42 secretion and Aβ42/40 ratio [41, 42]	Compound E, an γ-secretase inhibitor [41]
	PS1 mutations	Increased production of endogenous Aβ40 and increased Aβ42/40 ratio [141], APP processing, phosphor-tau, and activated GSK-3β [53, 159]; Diminished autophagy degradation, lysosomal abnormalities, impaired mitophagy [160]; Increased content of BRCA1(Ser1524) [161]
	PSEN2 N141I mutation	Increased Aβ42, enhanced ratio of Aβ42/40, elevated phosphor-Tau and GSK3β, impaired insulin signaling [162]
	APPDp	Increased Aβ40, phosphor-tau, and activated GSK-3β, increased RAB5-positive endosomes [43]	β-secretase inhibitors (βSi-II and OM99–2) [43]
	APP-E693Δ	ER stress and oxidative stress, increased apoptotic markers [45]	docosahexaenoic acid (DHA) [45]
	APPV717I	Increased Aβ42, APP processing, enhanced tau phosphorylation [163]	Aβ antibody [163]
	ApoE4	Increased tau phosphorylation, GABAergic neuron degeneration [50];; Increased synapse number and elevated Aβ42 secretion in neurons whereas impaired Aβ uptake and cholesterol accumulation in astrocytes [164] [165]	PH002, an ApoE structure corrector [50]; HDAC3 inhibitor [165]
	Sporadic	Increased Aβ42, elevated ratio of Aβ42/40, oxidative stress [45]; hyper-phosphor Tau and activated GSK3β [43, 54]	Cdk2 inhibitor [142]; An anti-Aβ cocktail ( bromocriptine, cromolyn, and topiramate) [143];
Parkinson’s disease	LRRK2 mutation (G2019S)	Oxidative stress and increased amount of α-synuclein, sensitive to caspase-3 activation and cellular stressors [58, 66]; Reduced numbers of neurites and neurite arborization, and impaired autophagy [63]; Impairment of mitochondrial respiration [59], mtDNA [61] and trafficking [62]; Excessive mitochondrial fragmentation, enhanced autophagy and neurite shortening of DA neurons [60].	Coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074 [59]; P110, a peptide inhibitor of Drp1-Fis1 [60]
	α-synuclein A53T	Nitrosative stress and ER stress [70, 71], and mitochondrial damage and impaired mitophagy [73]; α-synuclein aggregation [76], and phosphorylation [85]	Isoxazole [125]
	α-Synuclein triplication	Oxidative stress [79]; Lower lysosomal degradation capacity [80]; Reduced capacity to differentiate into DA or GABAergic neurons, decreased neurite outgrowth and lower neuronal activity [81]; ER stress [82] and α-synuclein phosphorylation [85]
	PINK1	Impaired recruitment of Parkin to mitochondria, increased mitochondrial copy number, and upregulated PGC-1α [87]. Decreased mitochondrial membrane potential [87, 88], mitochondrial complex I activity[89, 90], and deficient mitochondrial trafficking [62]	Rapamycin and GW5074 [59]
	Parkin	Decreased DA uptake and increased spontaneous DA release 91]; Oxidative stress, α-synuclein accumulation [92]; Abnormalities in endosomal processes and trafficking [93]; Disrupted calcium shuttling between mitochondria and ER [94]; Enhanced sensitivity to metal toxins [95, 96]; Abnormal neurite outgrowth and complexity [97]
	GBA	Elevated α-synuclein protein levels, reduced capacity to synthesize and release dopamine, increased monoamine oxidase B [166, 167]; ER stress and abnormal cellular lipid profile, impaired autophagy and lysosome activity 167]
Huntington’s disease	mtHtt	Mitochondrial dysfunction and enhanced caspase activity upon growth factor deprivation [102–104]; Mitochondrial fragmentation and neurite shortening of medium spiny neurons [145, 146]; DNA damage [148]; Increased vulnerability to stress/toxicity 104]; Lysosomal dysregulation and impaired cholesterol biosynthesis pathway [106, 107]; Oxidative stress and reduced cytoskeleton- associated proteins [108].	P110, a peptide inhibitor of Drp1-Fis1 interaction [145]; HV-3, a peptide blocker of mtHtt-VCP interaction[146]; Bexarotene, a potent retinoid X receptor agonist [147]; KU55933, an ATM protein inhibitor [148]; CGS-21680 and APEC, adenosine receptor 2A agonists [149].
ASL	SOD1	Reduced soma size and altered dendrite length of motor neurons, and dysregulated neurofilaments [119]; Impaired mitochondrial function and structure [120]; ER stress [120] and neuronal hyperexcitability [121];	Retigabine, a clinically approved anticonvulsant [121]
	TDP-43	Cytosolic aggregates of TDP-43 and shorter neurites of motor neurons[133–135];; Increased vulnerability in a variety of stressors [134, 135], Mitochondrial fragmentation and mitochondrial bioenergetics deficiency [136].	PM1, a peptide inhibitor of TDP-43 mitochondrial localization [136]; Digoxin [137]; Anacardic acid, a histone acetyltransferase inhibitor [44]
	C9ORF72	Increased transcription of C9ORF72, accumulation of GGGGCC repeat-containing RNA foci, susceptibility to excitotoxicity [124– 127]; Impaired endosomal trafficking and autophagy [129–131]	Antisense oligonucleotide (ASO) to the C9ORF72 [124, 126, 150]