Table 2. Selected examples of multigenic neurological diseases modeled with patient-specific iPSCs.

Disease	Genetic defects	iPSC-derived cell types	Phenotype demonstrated	Genetic rescue	Drug test	References
Amyotrophic lateral sclerosis (ALS)	Mutation in SOD1 Mutation in VAPB Mutation in TDP-43	Motor neurons Motor neurons Motor neurons	No answer Reduced VAPB expression in motor neurons. Formation of cytosolic TDP-43 aggregates; Decreased neurite length; Increased vulnerability to antagonism of the PI3K pathway and oxidative stressors.	No No No	No No Yes	36,65 97 37,38
Rett syndrome (RTT)	Mutation in MECP2 Mutation in CDKL5	Neurons Glutamatergic neurons	Decreased synapse number, spine number and soma size; Elevated LINE1 retrotransposon mobility. Aberrant dendritic spine structure.	No No	No No	98,99,100 101 102
Parkinson's disease (PD)	Mutation in LRRK2 Mutation in PINK1 Mutation in SNCA Mutation in PARKIN	Dopaminergic neurons and neural stem cells Dopaminergic neurons Dopaminergic neurons Dopaminergic neurons	Increased SNCA levels and vulnerability to stress agents; Passage-dependent deficiencies in nuclearenvelope organization, clonal expansion and neuronal differentiation. Impaired recruitment of Parkin to mitochondria, increased mitochondrial copy number and upregulation of PGC-1α Increased vulnerability to cellular stressors. Increased SNCA expression and susceptibility to oxidative stress. Mitochondrial dysfunction associated with increased oxidative stress and SNCA accumulation.	Yes Yes No No	Yes Yes No Yes	44,45,46 103 47 46 42,43 48
Alzheimer's disease (AD)	Mutations in PS1 and PS2 Duplication of APP	Neurons Neurons	Increased ratio of Aβ42/40. Increased Aβ40 production, phospho-Tau and GSK-3β activity.	No No	Yes Yes	32,104 30,31