Table 1.
List of published studies modeling human neurological diseases with iPSCs
| Disease | References | Patient genotype | Cell type analyzed | Identified phenotype | Notable |
|---|---|---|---|---|---|
| Alzheimer's Disease | Yagi et al (2011) | PSEN1, PSEN2 mutations | Neurons | Increased amyloid β42 secretion | |
| Alzheimer's Disease | Israel et al (2012) | APP mutations, sporadic cases | Neurons | Increased amyloid β40, Tau and GSK3β phosphorylation, accumulation of endosomes | One of two sporadic patients exhibited phenotypes |
| Alzheimer's Disease | Kondo et al (2013) | APP mutations, sporadic cases | Cortical neurons, astrocytes | Accumulated Aβ oligomers, ER & oxidative stress | One of two sporadic patients exhibited phenotypes |
| Alzheimer's Disease | Muratore et al (2014) | APP mutation | Forebrain neuron | Increase in Aβ42, Aβ38, pTAU | Aβ-antibodies reduce pTAU |
| Alzheimer's Disease | Sproul et al (2014) | PSEN1 mutation | Neural progenitors | Higher Aβ42/Aβ40 ratio, gene expression differences | Verification of gene expression differences in human AD brains |
| Alzheimer's Disease | Duan et al (2014) | Sporadic ApoE3/E4 | Basal forebrain cholinergic neurons | Higher Aβ42/Aβ40 ratio, increased vulnerability to glutamate-stress | |
| Alzheimer's Disease | Hossini et al (2015) | Sporadic | Neurons | Gene expression analysis | |
| Amyotrophic Lateral Sclerosis (ALS) | Dimos et al (2008) | SOD1 mutations | Motor neurons | N.D. | First report of patient-specific neurons |
| Amyotrophic Lateral Sclerosis (ALS) | Mitne-Neto et al (2011) | VAPB mutations | Fibroblasts, iPSCs, motor neurons | Reduced VAPB protein levels | Although VAPB levels were highest in neurons, the reduction was not specific to neurons |
| Amyotrophic Lateral Sclerosis (ALS) | Bilican et al (2012) | TDP43 mutations | Motor neurons | Cell death | Real-time survival analysis of HB9+ neurons |
| Amyotrophic Lateral Sclerosis (ALS) | Egawa et al (2012) | TDP43 mutations | Motor neurons | Expression differences, TDP43 pathology, shorter neurites | Rescue by anacardic acid, multiple clones per patient used |
| Amyotrophic Lateral Sclerosis (ALS) | Sareen et al (2013) | C9orf72 expansion | Motor neurons | RNA foci, hypoexcitability, gene expression differences | Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-α, rescue of gene expression by ASO treatment |
| Amyotrophic Lateral Sclerosis (ALS) | Donnelly et al (2013) | C9orf72 expansion | Neurons | RNA foci, irregular interaction with ADARB2, susceptibility to glutamate excitotoxicity | Colocalization of repeat with ADARB2 validated in patient motor cortex. Rescue of gene expression by ASO treatment |
| Amyotrophic Lateral Sclerosis (ALS) | Yang et al (2013b) | SOD1, TDP43 mutations | Motor neurons | Sensitivity to growth factor withdrawal | Rescue by kenpaullone |
| Amyotrophic Lateral Sclerosis (ALS) | Serio et al (2013) | TDP43 mutations | Astrocytes | Cell death, TDP43 mislocalization | |
| Amyotrophic Lateral Sclerosis (ALS) | Wainger et al (2014) | SOD1, C9orf72, FUS mutations | Motor neurons | Hyperexcitability | Phenotype rescued by gene correction in SOD1, and by treatment with a Kv7 agonist |
| Amyotrophic Lateral Sclerosis (ALS) | Kiskinis et al (2014) | SOD1, C9orf72 mutations | Motor neurons | Cell death, reduced soma size, ER stress, mitochondrial abnormalities, gene expression changes | Phenotypes rescued by gene correction in SOD1 |
| Amyotrophic Lateral Sclerosis (ALS) | Chen et al (2014) | SOD1 mutations | Motor neurons | Neurofilament aggregation, cell death | Phenotype rescued by gene correction |
| Amyotrophic Lateral Sclerosis (ALS) | Barmada et al (2014) | TDP43 mutations | Neurons, astrocytes | Sensitivity to TDP43 accumulation | Autophagy stimulation increases survival |
| Amyotrophic Lateral Sclerosis (ALS) | Devlin et al (2015) | TDP43 and C9orf72 mutants | Neurons | Electrophysiological dysfunction | Hyperexcitability followed by loss of action potential output |
| Angelman & Prader–Willi Syndrome | Chamberlain et al (2010) | 15q11-q13 deletions | Neurons | UBE3A expression | Genomic imprint is maintained in iPSC neurons |
| Ataxia Telangiectasia | Lee et al (2013) | ATM mutations | NPCs & neurons | Defective DNA damage response | SMRT compounds rescue phenotype |
| Best Disease | Singh et al (2013) | BEST1 mutations | RPE cells | Delayed RHODOPSIN degradation, defective Ca2+ responses, oxidative stress | |
| Dravet Syndrome | Higurashi et al (2013) | SCN1A mutation | Neurons (mostly GABA+) | Reduced AP firing | |
| Dravet Syndrome | Liu et al (2013b) | SCN1A mutation | Neurons (GABA & Glutamate+) | Increase Na+ current density, altered excitability | |
| Dravet Syndrome | Jiao et al (2013) | SCN1A mutation | Neurons | Abnormal Na+ currents, increased firing | |
| Familial Dysautonomia | Lee et al (2009) | IKBKAP mutation | Peripheral neurons, neural crest precursors | Mis-splicing & IKBKAP expression, neurogenesis & migration defects | Phenotypes are tissue specific |
| Familial Dysautonomia | Lee et al (2012) | IKBKAP mutation | Neural crest precursors | IKBKAP expression levels | First large-scale drug screening approach, first follow-up study |
| Fragile X Syndrome | Sheridan et al (2011) | FMR1 expansion | NPCs & neurons | FMR1 promoter methylation & reduced expression, reduced length of processes | |
| Fragile X Syndrome | Liu et al (2012b) | FMR1 expansion | Neurons | Decreased PSD95 expression & density, neurite length, electrophysiological defects | |
| Fragile X Syndrome | Doers et al (2014) | FMR1 expansion | Neurons | Neurite extension & initiation defects | |
| Friedreich's Ataxia | Liu et al (2011) | FXN expansion | Peripheral neurons, cardiomyocytes | FXN expression, repeat instability | |
| Friedreich's Ataxia | Hick et al (2013) | FXN expansion | Neurons, cardiomyocytes | FXN expression, mitochondrial dysfunction | |
| Friedreich's Ataxia | Eigentler et al (2013) | FXN expansion | Peripheral neurons | FXN expression | |
| Frontotemporal Dementia | Almeida et al (2013) | C9orf72 expansion | Neurons | RNA foci, RAN products, sensitivity to autophagy inhibitors | |
| Frontotemporal Dementia (Bv) | Gascon et al (2014) | Sporadic patients | Neurons | Alterations in miR-124 & AMPAR levels | Confirmation of mouse model findings in iPSC neurons & patients |
| Frontotemporal Dementia | Raitano et al (2015) | PGRN mutation | Cortical & motor neurons | Cortical differentiation defects | Rescue by PGRN expression |
| Gaucher's Disease | Mazzulli et al (2011) | GBA1 mutations | Dopaminergic neurons | Declined proteolysis, increased α-synuclein | Provides links between GD & PD |
| Gaucher's Disease | Tiscornia et al (2013) | GBA1 mutations | Neurons & macrophages | Reduction in acid-β-glucosidase activity | Identification of two small molecules |
| Gyrate Atrophy | Meyer et al (2011) | OAT mutation | RPE cells | Decreased OAT activity | Rescued by BAC-mediated introduction of OAT |
| Hereditary Spastic Paraplegia | Denton et al (2014) | SPAST mutation | Glutamatergic neurons | Axonal swelling, increased levels of acetylated tubulin | |
| Hereditary Spastic Paraplegia | Zhu et al (2014) | ATL1 mutation | Forebrain neurons | Impaired axonal growth, defects in mitochondrial motility | |
| Huntington's Disease | Camnasio et al (2012) | HTT expansion | Neurons | Altered lysosomal activity | |
| Huntington's Disease | Juopperi et al (2012) | HTT expansion | Astrocytes | Cytoplasmic vacuolization | |
| Huntington's Disease | HD Consortium (2012) | HTT expansion | NPCs & GABA+ neurons | Altered gene expression, morphological alterations, survival deficit, sensitivity to stressors | Correlation between repeat length & vulnerability to cell stress |
| Huntington's Disease | An et al (2012) | HTT expansion | NPCs, neurons | Cell death, gene expression, mitochondrial dysfunction | Genetic correction rescued phenotypes |
| Huntington's Disease | Guo et al (2013) | HTT expansion | Neurons (GABA+) | Mitochondrial damage | |
| Huntington's Disease | Yao et al (2015) | HTT expansion | Striatal neurons | Cell death, caspase-3 activation | Identified Gpr52 as a stabilizer of HTT |
| Lesch–Nyhan Syndrome | Mekhoubad et al (2012) | HPRT1 mutation | Neurons | Neuronal differentiation efficiency and neurite number defects | Demonstrate that X-inactivation erodes in culture & could affects modeling of X-linked disease |
| Microcephaly | Lancaster et al (2013) | CDK5RAP2 mutation | Cerebral organoids | Smaller neuroepithelial regions & RGs, premature neurogenesis, RG spindle disarray | Generated 3-dimensional brain structures |
| Neuronal ceroid lipofuscinosis | Lojewski et al (2014) | CNL2, CNL3 mutations | NPCs, neurons | Morphological abnormalities in ER, Golgi, mitochondria & lysosomes | Rescue by expression of NCL proteins |
| Niemann–Pick type C1 disease | Trilck et al (2013) | NPC1 mutation | NPCs & neurons | Accumulation of cholesterol | |
| Parkinson's Disease | Byers et al (2011) | SCNA triplication | Dopaminergic neurons | Oxidative stress, α-synuclein accumulation | |
| Parkinson's Disease | Nguyen et al (2011) | LRRK2 mutations | Dopaminergic neurons | Oxidative stress, α-synuclein accumulation, sensitivity to stress reagents | |
| Parkinson's Disease | Seibler et al (2011) | PINK1 mutations | Dopaminergic neurons | Increased mitochondrial copy number, PGC1a upregulation | Rescue by PINK1 overexpression |
| Parkinson's Disease | Devine et al (2011) | SNCA triplication | Dopaminergic neurons | Upregulation of α-synuclein | |
| Parkinson's Disease | Sanchez-Danes et al (2012) | Sporadic & LRRK2 mutations | Dopaminergic neurons | Reduction in neurite number & density, vacuolization, sensitivity to lysosomal inhibition | A total of 15 patients examined, long-term culture ∽75 DIV |
| Parkinson's Disease | Cooper et al (2012) | PINK1 & LRRK2 mutations | Dopaminergic neurons | Mitochondrial dysfunction in response to stressors | Pharmacological rescue of phenotypes |
| Parkinson's Disease | Imaizumi et al (2012) | PARK2 mutations | Dopaminergic neurons | Oxidative stress, mitochondrial dysfunction, Nrf2 induction, α-synuclein accumulation | |
| Parkinson's Disease | Liu et al (2012a) | LRRK2 mutation | Neural stem cells | Susceptibility to proteosomal stress, differentiation & clonal expansion deficiencies | Genetic correction rescued phenotypes |
| Parkinson's Disease | Reinhardt et al (2013) | LRRK2 mutation | Dopaminergic neurons | Gene expression differences, ERK phosphorylation & activity | Genetic correction rescued phenotypes |
| Parkinson's Disease | Su and Qi (2013) | LRRK2 mutation | Dopaminergic neurons | Mitochondrial damage, shorter neuritis, lysosomal hyperactivity | Pharmacological rescue |
| Parkinson's Disease | Chung et al (2013) | SNCA mutation | Cortical neurons | Nitrosative & ER stress | Pharmacological rescue, combination between a yeast and an iPSC platform |
| Parkinson's Disease | Miller et al (2013) | PINK1 & PARKIN mutations | Dopaminergic neurons | TH reduction, dendritic degeneration | Phenotypes induced only after overexpressing progerin |
| Parkinson's Disease | Ryan et al (2013) | SNCA mutation | Dopaminergic neurons | Nitrosative stress, gene expression alterations, mitochondrial stress | Genetic & pharmacological rescue of phenotypes |
| Parkinson's Disease | Flierl et al (2014) | SNCA triplication | NPCs | Viability, metabolism & stress resistance defects | Rescue by SNCA knockdown |
| Parkinson's Disease | Sanders et al (2014) | LRRK2 mutations | NPCs & neurons | Mitochondrial DNA damage | Genetic correction rescued phenotypes |
| Phelan–McDermid Syndrome | Shcheglovitov et al (2013) | 22q13.3 deletion | Forebrain neurons | Defective excitatory synaptic transmission | Rescue by SHANK3 expression or IGF1 treatment |
| Retinitis Pigmentosa | Jin et al (2011) | RP1, RP9, PRPH2, RHO mutations | Rod photoreceptors | Cell death, oxidative & ER stress | Differential response to treatment with α-Tocopherol |
| Retinitis Pigmentosa | Tucker et al (2011) | MAK mutations | Retinal precursors | Defective MAK mRNA splicing | |
| Retinitis Pigmentosa | Jin et al (2012) | RHO mutations | RPE cells | Cell death & ER stress | |
| Retinitis Pigmentosa | Tucker et al (2013) | USH2A mutations | Retinal precursors | USH2A transcript defects, ER stress | |
| Rett Syndrome | Marchetto et al (2010) | MeCP2 mutations | Neurons | MeCP2 expression, reduced synapses, spine density, soma size, altered calcium signaling | |
| Rett Syndrome | Ananiev et al (2011) | MeCP2 mutations | Neurons | Reduced nuclear size | |
| Rett Syndrome | Cheung et al (2011) | MeCP2 deletion | Neurons | MeCP2 expression, reduced soma size | |
| Rett Syndrome | Kim et al (2011c) | MeCP2 mutations | Neurons | Lower TUJ1 & Na+ channel expression | |
| Rett Syndrome | Amenduni et al (2011) | CDKL5 mutations | Neurons | No phenotype described | |
| Rett Syndrome | Ricciardi et al (2012) | CDKL5 mutations | Neurons | Aberrant dendritic spines | |
| Rett Syndrome | Larimore et al (2013) | MeCP2 mutations | Neurons | Reduced expression of PLDN | |
| Rett Syndrome | Griesi-Oliveira et al (2014) | TRPC6 mutation | NPCs & cortical neurons | Gene expression differences, Ca2+ influx defects, decreased axonal length & arborization | Overlap in molecular pathways between TRPC6 & MeCPT2 |
| Rett Syndrome | Williams et al (2014) | MeCP2 mutations | Astrocytes | Mutant astrocytes cause morphological and firing defects in healthy neurons | Demonstrates non-cell autonomous contribution of astrocytes in Rett Syndrome |
| Rett Syndrome | Djuric et al (2015) | MeCP2e1 mutation | Cortical neurons | Reduced soma size, dendritic density, capacitance & firing defects | Rescue of phenotypes by overexpression of MeCP2e1 |
| Rett Syndrome | Livide et al (2015) | MeCP2 & CDKL5 mutations | NPCs & neurons | Gene expression differences | Identified GRID1 as a common target in two distinct genetic classes of RTT |
| Schizophrenia | Brennand et al (2011) | Familial & sporadic SCZD patients | NPCs & neurons | Decreased connectivity, neurite number, PSD95 protein, gene expression changes | Recovery after treatment with loxapine |
| Schizophrenia | Pedrosa et al (2011) | 22q11.2 deletion & sporadic SCZD | Glutamatergic neurons | No phenotype described | |
| Schizophrenia | Paulsen Bda et al (2012) | SCZD patient | NPCs | Elevated ROS, extramitochondrial consumption | Treatment with valproic acid reduced ROS |
| Schizophrenia | Robicsek et al (2013) | SCZD patients | NPCs, dopaminergic, glutamatergic neurons | Differentiation & maturation deficiencies, mitochondrial defects | |
| Schizophrenia | Yoon et al (2014) | 15q11.2 microdeletion | NPCs | Deficits in adherent junctions & apical polarity | Identified haploinsufficiency of CYFIP1 as a potential contributor to neuropsychiatric disorders |
| Schizophrenia | Hook et al (2014) | SCZD patients | Neurons | Increased secretion of catecholamines, higher numbers of TH+ neurons | |
| Schizophrenia | Wen et al (2014b) | DISC1 mutations | Forebrain neurons | Synaptic vesicle release deficits, gene expression changes | Isogenic controls included in this study |
| Schizophrenia | Brennand et al (2015) | Familial & sporadic SCZD patients | NPCs & neurons | RNA & protein-level differences related to cytoskeleton & oxidative stress, aberrant migration | |
| Spinal Muscular Atrophy | Ebert et al (2009) | Type 1 SMA | Motor neurons | Cell death, soma size, reduced SMN levels | First study of iPSC-based approach to report a disease-associated phenotype |
| Spinal Muscular Atrophy | Sareen et al (2012) | Type 1 SMA | Motor neurons | Cell death, increased caspase-8 & 3 activation | Rescue by apoptotic inhibitors |
| Spinal Muscular Atrophy | Corti et al (2012) | Type 1 SMA | Motor neurons | Cell death, smaller soma size, reduced axonal length, gene expression and RNA splicing defects | Gene correction, transplantation of iPSC motor neurons extends lifespan of SMA mouse model |
| Tauopathy | Fong et al (2013) | TAU mutation | Neurons | TAU fragmentation & phosphorylation, axonal degeneration | Gene editing to correct the mutation & generate a homozygous mutant used as controls |
| Timothy Syndrome | Pasca et al (2011) | CACNA1C mutations | NPCs & cortical neurons | Ca2+ signaling, activity-dependent gene expression | Rescue by roscovitine treatment |
| Timothy Syndrome | Krey et al (2013) | CACNA1C mutations | Cortical neurons | Activity-dependent dendrite retraction | Rescue by GTPase Gem |
NPCs, neural progenitor cells; RPE, retinal pigment epithelium; ND, not determined; ASO, allele-specific oligonucleotide; GD, Gaucher's disease; PD, Parkinson's disease; AP, action potential.
The table includes neurodevelopmental and neurodegenerative diseases for which patient-specific iPSCs have been generated and neuronal cells differentiated to develop a cell-based model of disease.