Table S1: Human embryonic stem cell models of neurodegeneration.

Disease / Original cell type / Mutation in original cell type / Genetic modification / Cell type analyzed / Disease phenotype / Reference
Alzheimer`s disease / Human ES cells / Trisomy 21 / No / Cortical neurons / Increased production of Aβ40 and Aβ42; increased Aβ42/40 ratio;
intracellular and extracellular aggregates of Aβ42 protein;
increased expression of phospho-Tau (Ser202, Thr205, Thr231 and Ser396), redistribution and mislocalization of tau protein / Shi et al., 2012
Huntington`s disease / Human ES cells / CAG repeats (4 heterozygous lines with 40, 45, 46 or 48 repeats) in HTT gene / No / Undifferentiated human ES cells; neurons / not analyzed / Bradley et al., 2011
Human ES cells / CAG repeats (1 heterozygous line with 44 repeats) in HTT gene / No / Undifferentiated human ES cells / not analyzed / Mateizel et al., 2006
Human ES cells / CAG repeats (2 heterozygous lines with 37 or 51 repeats) in HTT gene / No / Undifferentiated human ES cells; forebrain neurons / Elevated glutamate-evoked response with increased [Ca2+]i levels in neurons derived from human ES cells with 51 HTT repeats / Verlinsky et al., 2005; Niclic et al., 2009 and 2013
Parkinson`s disease / Human ES cells
(lines BG01; WIBR3) / No / Introduction of the E46K-SNCA mutation in undifferentiated ES cells via zinc finger nuclease-mediated gene transfer / Undifferentiated human ES cells / not analyzed / Soldner et al.,
2011
Human ES cells
(lines BG01; WIBR3) / No / Introduction of the A53T-SNCA mutation in undifferentiated ES cells via zinc finger nuclease-mediated gene transfer / Undifferentiated human ES cells; dopaminergic neurons / not analyzed / Soldner et al.,
2011

Table S2: Human stem cell models of neurodegeneration using patient-derived iPS cells.

Disease / Gene (Mutation) / Cell type analyzed / Disease
phenotype / Rescue of disease phenotype / Reference
Alzheimer`s disease / Sporadic / Neurons / In one differentiated sporadic iPS cell line increased levels of secreted Aβ40 protein, phospho-tau (Thr231) and active GSK-3β; accumulation of RAB5-positive endosomes within neurons / Decreased levels of secreted Aβ40 protein, phospho-tau (Thr231) and active GSK-3β after application of β-secretase inhibitors;
decreased levels of secreted Aβ40 protein after application of γ-secretase inhibitors / Israel et al., 2012
APP (duplication of the amyloid-β precursor protein gene) / Neurons / Increased levels of secreted Aβ40 protein, phospho-tau (Thr231) and active GSK-3β; accumulation of RAB5-positive endosomes within neurons / Decreased levels of secreted Aβ40 protein, phospho-tau (Thr231) and active GSK-3β after application of β-secretase inhibitors;
decreased levels of secreted Aβ40 protein after application of γ-secretase inhibitors / Israel et al., 2012
APP
(E693Δ)
Sporadic / Neurons, astrocytes / Aβ protein accumulation in neurons and astrocytes; increased oxidative stress / Improvement of stress response after application of docosahexaenoic acid / Kondo et al., 2013
Presenilin 1 and 2
(PS1 A246E)
(PS2 N141I) / Neurons / Increased Aβ42/40 ratio
/ Decrease of elevated Aβ42/40 ratio after inhibition of
γ-secretase / Yagi et al.,
2011
Trisomy 21 / Cortical neurons / Increased production of Aβ40 and Aβ42; increased Aβ42/40 ratio;
intracellular and extracellular aggregates of Aβ42 protein;
increased expression of phospho-Tau (Ser202, Thr205, Thr231 and Ser396); redistribution and mislocalization of tau protein / Reduction of Aβ40 and Aβ42 protein production after application of the γ-secretase inhibitor DAPT / Shi et al.,
2012
Parkinson`s
disease / Sporadic / iPS cells / Characterization of iPS cells only / not described / Park et al., 2008
Sporadic / Dopaminergic neurons / No differences in DA neuronal differentiation detected / not described / Soldner et al., 2009
Sporadic / Dopaminergic neurons / Reduced number of neurites, reduced neurite arborization and neurite length; increased expression of caspase 3 after prolonged culture in vitro;
increased vulnerability to MPP+ / not described / Sánchez-Danés et al., 2012
LRRK-2
(G2019S) / Dopaminergic neurons / Reduced neurite outgrowth; increased accumulation of SNCA protein / not described / Nguyen et al., 2011
LRRK-2
(G2019S) / Dopaminergic neurons / Reduced neurite outgrowth; increased expression of stress-response genes after prolonged culture; increased accumulation of SNCA protein; impaired clearance of autophagosomes / not described / Sánchez-Danés et al., 2012
LRRK-2
(G2019S) / Neural precursor cells / Disturbances in nuclear envelope organization; passage-dependent modifications in epigenetic signatures / Reversal of disease phenotypes by zinc finger-mediated gene transfer; via LRRK2 inhibition / Liu et al., 2012*
LRRK-2
(G2019S) / Dopaminergic neurons / Increased vulnerability to valinomycin and concanamycin A / Partial rescue of phenotypes through application of rapamycin, coenzyme Q10 and a LRRK2 kinase inhibitor / Cooper et al., 2012
LRRK-2
(G2019S) / Dopaminergic neurons / Reduced neurite outgrowth; increased accumulation of SNCA and MAPT protein; dysregulation of proteins associated with neurodegeneration; increased vulnerability to rotenone and H2O2 / Reversal of disease phenotypes by zinc finger-mediated gene transfer; via inhibition of MAPK/ERK pathway / Reinhardt et al., 2013a*
LRRK-2
(G2019S) / Dopaminergic neurons / Increased vulnerability to rotenone / not described / Reinhardt et al., 2013b
LRRK-2
(G2019S) / Dopaminergic neurons / Disturbed chaperone-mediated autophagy / not described / Orenstein et al., 2013
LRRK-2
(G2019S) / Neural
cells / Increased levels of mitochondrial DNA damage / Reversal of disease phenotype by zinc finger-mediated gene transfer / Sanders et al., 2013*
LRRK-2
(R1441C) / Dopaminergic neurons / Dysfunctional intracellular transport of mitochondria; increased vulnerability to valinomycin and concanamycin A / Partial rescue of phenotypes through application of rapamycin, coenzyme Q10 and a LRRK2 kinase inhibitor / Cooper et al., 2012
LRRK-2
(R1441C) / Neural
cells / Increased levels of mitochondrial DNA damage / not described / Sanders et al., 2013
SNCA (triplication) / Dopaminergic neurons / Increased amount of SNCA protein / not described / Devine et al., 2011
SNCA (triplication) / Dopaminergic neurons / Increased amount of SNCA protein; increased expression of stress response genes; increased vulnerability to H2O2 / not described / Byers et al., 2011
SNCA (triplication) / Neurons / Increased expression of SNCA protein / not described / Yagi et al.,
2012
SNCA
(A53T) / iPS cells / Characterization of iPS cells before and after zinc finger-mediated correction of genetic defect in SNCA gene / not described / Soldner et al.,
2011*
SNCA
(A53T) / Cortical neurons / Accumulation of nitric oxide and ER-associated substrates glucocerebrosidase and nicastrin; increased ER-stress / Reversal of substrate accumulation by application of NAB2 and overexpression of Nedd4; zinc finger-mediated gene transfer to generate isogenic lines / Chung et al., 2013*
PINK1
(C136T; T509G) / Dopaminergic neurons / 80% reduction of PINK1 levels in mutated neurons; impaired recruitment of Parkin to mitochondria; increased mitochondrial biogenesis upon mitochondrial depolarization / Rescue of phenotypes by overexpression of wt PINK1 in mutated iPS cell-derived neurons / Seibler et al., 2011
PARKIN
(homozygous deletion of exon 3;
compound heterozygous deletion of exons 3 and 5) / Dopaminergic neurons / Increased dopamine release and reduced dopamine uptake / Rescue of phenotypes by overexpression of wt Parkin in mutated iPS cell-derived neurons / Jiang et al., 2011
PARKIN
(homozygous deletion of exons 2-4;
homozygous deletion of exons 6 and 7) / Neurons / Increased oxidative stress; enhanced expression of Nrf2 and NQO1; altered morphology of mitochondria and impaired mitochondrial homeostasis; accumulation of SNCA protein in iPS cell-derived neurons generated from a patient who presented with Lewy bodies / not described / Imaizumi et al., 2012
Amyotrophic lateral sclerosis / Sporadic / Motor neurons / Accumulation of TDP-43 protein in motor neurons / Reduction of TDP-43-positive aggregates after application of digoxin / Burkhardt et al., 2013
SOD1
(superoxide dismutase 1)
(L144F) / iPS cells, astrocytes and motor neurons / not described / not described / Dimos et al., 2008
SOD1
(L144F)
(G85S) / iPS cells and motor neurons / No differences in motor neuron differentiation detected; however, 2 ALS-iPS and 1 control iPS cell line required alternative differentiation protocol to derive motor neurons / not described / Boulting et al., 2011
VAPB/C
(P56S) / Motor neurons / Decreased levels of VAPB protein but normal VAPB mRNA expression levels / not described / Mitne-Neto et al., 2011
TDP-43
(TAR-DNA binding protein-43)
(M337V) / iPS cells and motor neurons / Accumulation of soluble and detergent-resistant TDP-43 protein in iPS cells and motor neurons; decreased survival of motor neurons during culture; increased vulnerability of motor neurons after PI3K inhibiton / not described / Bilican et al., 2012
TDP-43
(Q343R)
(M337V)
(G298S) / Motor neurons / Increased TDP-43 mRNA and detergent-insoluble TDP-43 protein; cytosolic TDP-43-positive aggregate formation; intranuclear aggregates of TDP-43/SNRPB2 proteins; decreased neurite length; increased expression of genes involved in RNA metabolism; decreased expression of genes encoding cytoskeletal proteins; increased vulnerability to arsenite / Reversal of disease phenotypes through the histone acetyl transferase inhibitor anacardic acid / Egawa et al., 2012
TDP-43
(M337V) / Astrocytes / Accumulation of soluble TDP-43 protein; cytoplasmic localization of TDP-43 protein; decreased cell survival / not described / Serio et al., 2013
SOD1
(L144F)
TDP-43
(M337V) / Motor neurons / Cell death upon withdrawal of neurotrophic factors / Increase in motor neuron survival after application of the kinase inhibitor kenpullone / Yang et al., 2013
C9ORF72 / Motor neurons / Accumulation of RNA foci; altered gene expression; changes of electrophysiology-cal responses in neurons / Suppressed formation of RNA foci and reversal of altered gene expression after application of antisense oligonucleotides targeting C9ORF72 / Sareen et al., 2013
Frontotemporal dementia / Sporadic / Cortical neurons and microglia / Increased sensitivity to tunicamycin / not described / Almeida et al., 2012
Progranulin
(S116X) / Cortical neurons and microglia / Increased sensitivity to staurosporine, tunicamycin and wortmannin; downregulation of the serine/threonine kinase S6K2 / Overexpression of PRGN gene and reversal of stress phenotypes / Almeida et al., 2012
MAPT
(A152T) / Neurons / Fragmentation and phosphorylation of tau protein (Ser 202 and Thr 205) / Genetic correction and partial reversal of disease phenotypes / Fong et al., 2013*
C9ORF72 / Cortical neurons / Instability of GGGGCC repeat expansions; intracellular RNA foci and repeat-associated non-ATG translation products; accumulation of p62; compromised autophagy function / not described / Almeida et al., 2013
C9ORF72 / Neurons / Intranuclear RNA foci; sequestration of RNA-binding protein ADARB2; repeat-associated non-ATG translation (RAN) products; dysregulated gene expression; increased vulnerability to glutamate / Reduced number of RNA foci after siRNA-mediated knockdown of ADARB2; reduced RNA toxicity after application of antisense oligonucleotides targeting either the intronic GGGGCC repeat sequence or a downstream sequence in exon 2 of C9ORF72 / Donnelly et al., 2013
Huntington`s disease / Huntingtin
(72 CAG repeats) / iPS cells / Characterization of iPS cells only / not described / Park et al., 2008
Huntingtin
(72 CAG repeats) / Neural precursor cells / Increased caspase activity upon growth factor deprivation / not described / Zhang et al., 2010
Huntingtin
(45 CAG repeats;
2 patients with homozygous CAG expansions: 42/44 and 39/43 repeats) / iPS cells and neurons / Increased lysosomal content and increased autophagosome formation / not described / Camnasio et al., 2012
Huntingtin
(72 CAG repeats) / iPS cells and neurons / Intracellular aggregates of huntingtin after application of proteasome inhibitor MG-132 to iPS cells and in iPS cell-derived cells 33 weeks after transplantation into lateral ventricle of postnatal mice / not described / Jeon et al., 2012**
Huntingtin
(72 CAG repeats) / iPS cells and neurons / Decreased differentiation into neurons;
reduced neurite outgrowth; increased apoptosis; downregulation of cytoskeleton-associated proteins in neurons;
proteome analysis in iPS cells revealing 26 misregulated proteins including upregulation of Prx family stress response proteins and downregulation of antioxidant enzymes SOD, GST and Gpx1 / not described / Chae et al., 2012
Huntingtin
(72 CAG repeats) / Neural precursor cells / Upregulation of TGF-β pathway genes and downregulation of cadherin family genes;
increased apoptosis and expression of caspase 3/7 upon growth factor deprivation;
decreased BDNF expression;
oxygen consumption rate decreased / Genetic correction and reversal of disease phenotypes / An et al., 2012*, **
Huntingtin
(60, 109 and 180 CAG repeats) / Neural precursor cells,
neurons / Decreased cell adhesion;
decreased energy metabolism;
increased cell death after prolonged culture;
dysregulation of genes involved in proliferation, cell signaling and cellular assembly;
increased cell death after withdrawal of BDNF and after application of glutamate, H202 and 3-MA;
phenotypes in part dependent on length of CAG repeats / not described / HD iPSC Consortium; 2012
Huntingtin
(72 CAG repeats) / Neurons / Intracellular aggregates of huntingtin after application of proteasome inhibitor MG-132 to iPS cells / Lack of pathological aggregates after overexpression of
miR-196a / Cheng et al., 2013
Spinal muscular atrophy / SMN1
(deletion of exons 7 and 8) / Fibroblasts; iPS cells; motor neurons / Reduced level of SMN mRNA in fibroblasts and iPS cells; reduced number and size of motor neurons and reduced synaptic punctae after prolonged culture of motor neurons; reduced number of SMN-positive nuclear gems in iPS cells and neurons / Increased number of gems and increased expression of SMN protein after application of valproic acid and tobramycin / Ebert et al., 2009
SMN1
(deletion of exons 7 and 8) / Motor neurons / Reduced number and size of motor neurons after prolonged culture; increased apoptosis and increased expression of cleaved caspase-3, cleaved caspase-8 and membrane-bound Fas / Improved survival of motor neurons through long-term blockage of Fas with antagonistic monoclonal antibody and through caspase-3 inhibition / Sareen et al., 2012
SMN1
(deletion of exons 7 and 8) / iPS cells,
motor neurons / In comparison to hES cell line H9 reduced number of nuclear SMN-positive gems; reduced number of motor neurons and delayed neurite outgrowth / Rescue of phenotypes by overexpression of SMN protein in iPS cells / Chang et al., 2011
SMN1 / iPS cells,
motor neurons / Reduced number of SMN-positive gems in iPS cells and of SMN protein in iPS cells and motor neurons; reduced number and size of motor neurons after prolonged culture; reduced neurite outgrowth; fewer and smaller neuromuscular junctions; altered expression of genes involved in RNA metabolism, motor neuron development and axonal guidance; reduced engraftment after transplantation into mouse model of SMA / Reversal of most phenotypes after genetic correction of iPS cells via single stranded oligonucleotide-driven conversion of SMN2 gene into SMN1-like gene / Corti et al., 2012*, **