Pluripotent stem cells for neurodegenerative disease modeling: an expert view on their value to drug discovery

References

• Group GBDNDC. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet Neurol. 2017 Nov;16(11):877–897.
   PubMed Web of Science ®Google Scholar
• Alzheimer’s A. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 2016 Apr;12(4):459–509.
   PubMedGoogle Scholar
• Grow DA, McCarrey JR, Navara CS. Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson’s disease. Stem Cell Res. 2016 Sep;17(2):352–366.
   PubMed Web of Science ®Google Scholar
• Eaton SL, Wishart TM. Bridging the gap: large animal models in neurodegenerative research. Mamm Genome. 2017 Aug;28(7–8):324–337.
   PubMed Web of Science ®Google Scholar
• Chakravarthy R, Cotter K, DiMasi J, et al. Public- and private-sector contributions to the research and development of the most transformational drugs in the past 25 years: from theory to therapy. Ther Innov Regul Sci. 2016 Nov;50(6):759–768.
   PubMed Web of Science ®Google Scholar
• Hay M, Thomas DW, Craighead JL, et al. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014 Jan;32(1):40–51.
   PubMed Web of Science ®Google Scholar
• Arneric SP, Kern VD, Stephenson DT. Regulatory-accepted drug development tools are needed to accelerate innovative CNS disease treatments. Biochem Pharmacol. 2018 May;151:291–306.
   PubMed Web of Science ®Google Scholar
• Cummings J. Lessons learned from Alzheimer disease: clinical trials with negative outcomes. Clin Transl Sci. 2018 Mar;11(2):147–152.
   PubMed Web of Science ®Google Scholar
• Maqsood MI, Matin MM, Bahrami AR, et al. Immortality of cell lines: challenges and advantages of establishment. Cell Biol Int. 2013 Oct;37(10):1038–1045.
   PubMed Web of Science ®Google Scholar
• Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998 Nov 6;282(5391):1145–1147.
   PubMed Web of Science ®Google Scholar
• Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007 Nov 30;131(5):861–872.
   PubMed Web of Science ®Google Scholar
• Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007 Dec 21;318(5858):1917–1920.
   PubMed Web of Science ®Google Scholar
• Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663–676.
   PubMed Web of Science ®Google Scholar
• Brennand KJ, Simone A, Tran N, et al. Modeling psychiatric disorders at the cellular and network levels. Mol Psychiatry. 2012 Dec;17(12):1239–1253.
   PubMed Web of Science ®Google Scholar
• Chambers SM, Fasano CA, Papapetrou EP, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009 Mar;27(3):275–280.
   PubMed Web of Science ®Google Scholar
• Lukovic D, Diez Lloret A, Stojkovic P, et al. Highly efficient neural conversion of human pluripotent stem cells in adherent and animal-free conditions. Stem Cells Transl Med. 2017 Apr;6(4):1217–1226.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Pak C, Han Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013 June 5;78(5):785–798.
   PubMed Web of Science ®Google Scholar
• Cheng C, Fass DM, Folz-Donahue K, et al. Highly expandable human iPS cell-derived neural progenitor cells (NPC) and neurons for central nervous system disease modeling and high-throughput screening. Curr Protoc Hum Genet. 2017 Jan 11;92:21 8 1–21 8 21.
   Google Scholar
• Chen C, Dong X, Fang KH, et al. Develop a 3D neurological disease model of human cortical glutamatergic neurons using micropillar-based scaffolds. Acta Pharm Sin B. 2019 May;9(3):557–564.
   PubMed Web of Science ®Google Scholar
• Chen YJ, Vogt D, Wang Y, et al. Use of “MGE enhancers” for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. PLoS One. 2013;8(5):e61956.
   PubMed Web of Science ®Google Scholar
• Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8 is involved in the determination of cholinergic or GABAergic cell fate. J Neurochem. 2005 Aug;94(3):723–730.
   PubMed Web of Science ®Google Scholar
• Lu H, Yu J, Wang J, et al. Simultaneous quantification of neuroactive dopamine serotonin and kynurenine pathway metabolites in gender-specific youth urine by ultra performance liquid chromatography tandem high resolution mass spectrometry. J Pharm Biomed Anal. 2016 Apr;15(122):42–51.
   Web of Science ®Google Scholar
• Ye W, Shimamura K, Rubenstein JL, et al. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell. 1998 May 29;93(5):755–766.
   PubMed Web of Science ®Google Scholar
• Sarkar A, Mei A, Paquola ACM, et al. Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro. Cell Stem Cell. 2018 May 3;22(5):684–697 e9.
   PubMed Web of Science ®Google Scholar
• Rajamani U, Gross AR, Hjelm BE, et al. Super-obese patient-derived iPSC hypothalamic neurons exhibit obesogenic signatures and hormone responses. Cell Stem Cell. 2018 May 3;22(5):698–712 e9.
   PubMed Web of Science ®Google Scholar
• Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011 Mar 4;8(3):267–280.
   PubMed Web of Science ®Google Scholar
• Xi J, Liu Y, Liu H, et al. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells. 2012 Aug;30(8):1655–1663.
   PubMed Web of Science ®Google Scholar
• Doi D, Samata B, Katsukawa M, et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Reports. 2014 Mar 11;2(3):337–350.
   PubMed Web of Science ®Google Scholar
• Samata B, Doi D, Nishimura K, et al. Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun. 2016 Oct 14;7:13097.
   PubMed Web of Science ®Google Scholar
• Kikuchi T, Morizane A, Doi D, et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature. 2017 Aug 30;548(7669):592–596.
   PubMed Web of Science ®Google Scholar
• Mali P, Chou BK, Yen J, et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells. 2010 Apr;28(4):713–720.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Wu WS. Sodium butyrate promotes generation of human induced pluripotent stem cells through induction of the miR302/367 cluster. Stem Cells Dev. 2013 Aug 15;22(16):2268–2277.
   PubMed Web of Science ®Google Scholar
• Liu P, Chen M, Liu Y, et al. CRISPR-based chromatin remodeling of the endogenous Oct4 or Sox2 locus enables reprogramming to pluripotency. Cell Stem Cell. 2018 Feb 1;22(2):252–261 e4.
   PubMed Web of Science ®Google Scholar
• Maury Y, Come J, Piskorowski RA, et al. Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat Biotechnol. 2015 Jan;33(1):89–96.
   PubMed Web of Science ®Google Scholar
• Guo W, Naujock M, Fumagalli L, et al. HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients. Nat Commun. 2017 Oct 11;8(1):861.
   PubMed Web of Science ®Google Scholar
• Hester ME, Murtha MJ, Song S, et al. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol Ther. 2011 Oct;19(10):1905–1912.
   PubMed Web of Science ®Google Scholar
• Fujimori K, Ishikawa M, Otomo A, et al. Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. Nat Med. 2018 Oct;24(10):1579–1589.
   PubMed Web of Science ®Google Scholar
• Erceg S, Ronaghi M, Zipancic I, et al. Efficient differentiation of human embryonic stem cells into functional cerebellar-like cells. Stem Cells Dev. 2010 Nov;19(11):1745–1756.
   PubMed Web of Science ®Google Scholar
• Salero E, Hatten ME. Differentiation of ES cells into cerebellar neurons. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2997–3002.
   PubMed Web of Science ®Google Scholar
• Muguruma K, Nishiyama A, Ono Y, et al. Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nat Neurosci. 2010 Oct;13(10):1171–1180.
   PubMed Web of Science ®Google Scholar
• Muguruma K, Nishiyama A, Kawakami H, et al. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 2015 Feb 3;10(4):537–550.
   PubMed Web of Science ®Google Scholar
• Watson LM, Wong MMK, Vowles J, et al. A simplified method for generating Purkinje cells from human-induced pluripotent stem cells. Cerebellum. 2018 Aug;17(4):419–427.
   PubMed Web of Science ®Google Scholar
• Sundberg M, Tochitsky I, Buchholz DE, et al. Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Mol Psychiatry. 2018 Nov;23(11):2167–2183.
   PubMed Web of Science ®Google Scholar
• Chandrasekaran A, Avci HX, Leist M, et al. Astrocyte differentiation of human pluripotent stem cells: new tools for neurological disorder research. Front Cell Neurosci. 2016;10:215.
   PubMed Web of Science ®Google Scholar
• Dezonne RS, Sartore RC, Nascimento JM, et al. Derivation of functional human astrocytes from cerebral organoids. Sci Rep. 2017 Mar;27(7):45091.
   Web of Science ®Google Scholar
• Tcw J, Wang M, Pimenova AA, et al. An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Reports. 2017 Aug 8;9(2):600–614.
   PubMed Web of Science ®Google Scholar
• Li X, Tao Y, Bradley R, et al. Fast generation of functional subtype astrocytes from human pluripotent stem cells. Stem Cell Reports. 2018 Oct 9;11(4):998–1008.
   PubMed Web of Science ®Google Scholar
• Nistor GI, Totoiu MO, Haque N, et al. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005 Feb;49(3):385–396.
   PubMed Web of Science ®Google Scholar
• Douvaras P, Wang J, Zimmer M, et al. Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports. 2014 Aug 12;3(2):250–259.
   PubMed Web of Science ®Google Scholar
• Piao J, Major T, Auyeung G, et al. Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell. 2015 Feb 5;16(2):198–210.
   PubMed Web of Science ®Google Scholar
• Czepiel M, Boddeke E, Copray S. Human oligodendrocytes in remyelination research. Glia. 2015 Apr;63(4):513–530.
   PubMed Web of Science ®Google Scholar
• Garcia-Leon JA, Kumar M, Boon R, et al. SOX10 single transcription factor-based fast and efficient generation of oligodendrocytes from human pluripotent stem cells. Stem Cell Reports. 2018 Feb 13;10(2):655–672.
   PubMed Web of Science ®Google Scholar
• Luo C, Lancaster MA, Castanon R, et al. Cerebral organoids recapitulate epigenomic signatures of the human fetal brain. Cell Rep. 2016 Dec 20;17(12):3369–3384.
   PubMed Web of Science ®Google Scholar
• Xiang Y, Tanaka Y, Patterson B, et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell. 2017 Sep 7;21(3):383–398 e7.
   PubMed Web of Science ®Google Scholar
• Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013 Sep 19;501(7467):373–379.
   PubMed Web of Science ®Google Scholar
• Sutcliffe M, Lancaster MA. A simple method of generating 3D brain organoids using standard laboratory equipment. Methods Mol Biol. 2019;1576:1–12.
   PubMedGoogle Scholar
• Grenier K, Kao J, Diamandis P. Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry. 2020 Feb;25(2):254–274.
   PubMed Web of Science ®Google Scholar
• Mich JK, Close JL, Levi BP. Putting two heads together to build a better brain. Cell Stem Cell. 2017 Sep 7;21(3):289–290.
   PubMed Web of Science ®Google Scholar
• Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014 Nov 13;515(7526):274–278.
   PubMed Web of Science ®Google Scholar
• Madhavan M, Nevin ZS, Shick HE, et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods. 2018 Sep;15(9):700–706.
   PubMed Web of Science ®Google Scholar
• Centeno EGZ, Cimarosti H, Bithell A. 2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling. Mol Neurodegener. 2018 May 22;13(1):27.
   PubMed Web of Science ®Google Scholar
• Ballard C, Gauthier S, Corbett A, et al. Alzheimer’s disease. Lancet. 2011 Mar 19;377(9770):1019–1031.
   PubMed Web of Science ®Google Scholar
• Muratore CR, Rice HC, Srikanth P, et al. The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014 July 1;23(13):3523–3536.
   PubMed Web of Science ®Google Scholar
• Israel MA, Yuan SH, Bardy C, et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature. 2012 Jan 25;482(7384):216–220.
   PubMed Web of Science ®Google Scholar
• Yang J, Zhao H, Ma Y, et al. Early pathogenic event of Alzheimer’s disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017 Jan 31;8(5):7900–7913.
   PubMedGoogle Scholar
• Liao MC, Muratore CR, Gierahn TM, et al. Single-cell detection of secreted Abeta and sAPPalpha from human IPSC-derived neurons and astrocytes. J Neurosci. 2016 Feb 3;36(5):1730–1746.
   PubMed Web of Science ®Google Scholar
• Oksanen M, Petersen AJ, Naumenko N, et al. PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Reports. 2017 Dec 12;9(6):1885–1897.
   PubMed Web of Science ®Google Scholar
• Lee HK, Velazquez Sanchez C, Chen M, et al. Three dimensional human neuro-spheroid model of Alzheimer’s disease based on differentiated induced pluripotent stem cells. PLoS One. 2016;11(9):e0163072.
   PubMed Web of Science ®Google Scholar
• Ochalek A, Mihalik B, Avci HX, et al. Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther. 2017 Dec 1;9(1):90.
   PubMed Web of Science ®Google Scholar
• Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018 June 27;98(6):1294.
   PubMed Web of Science ®Google Scholar
• Zhao J, Davis MD, Martens YA, et al. APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet. 2017 July 15;26(14):2690–2700.
   PubMed Web of Science ®Google Scholar
• Wang C, Najm R, Xu Q, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018 May;24(5):647–657.
   PubMed Web of Science ®Google Scholar
• Brownjohn PW, Smith J, Portelius E, et al. Phenotypic screening identifies modulators of amyloid precursor protein processing in human stem cell models of Alzheimer’s disease. Stem Cell Reports. 2017 Apr 11;8(4):870–882.
   PubMed Web of Science ®Google Scholar
• Kondo T, Imamura K, Funayama M, et al. iPSC-based compound screening and in vitro trials identify a synergistic anti-amyloid beta combination for Alzheimer’s disease. Cell Rep. 2017 Nov 21;21(8):2304–2312.
   PubMed Web of Science ®Google Scholar
• Mantle JL, Lee KH. Immunoglobulin G transport increases in an in vitro blood-brain barrier model with amyloid-beta and with neuroinflammatory cytokines. Biotechnol Bioeng. 2019 July;116(7):1752–1761.
   PubMed Web of Science ®Google Scholar
• Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol. 2016 Nov;15(12):1257–1272.
   PubMed Web of Science ®Google Scholar
• Reinhardt P, Schmid B, Burbulla LF, et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell. 2013 Mar 7;12(3):354–367.
   PubMed Web of Science ®Google Scholar
• Schwab AJ, Sison SL, Meade MR, et al. Decreased sirtuin deacetylase activity in LRRK2 G2019S iPSC-derived dopaminergic neurons. Stem Cell Reports. 2017 Dec 12;9(6):1839–1852.
   PubMed Web of Science ®Google Scholar
• Korecka JA, Talbot S, Osborn TM, et al. Neurite collapse and altered ER Ca(2+) control in human parkinson disease patient iPSC-derived neurons with LRRK2 G2019S mutation. Stem Cell Reports. 2019 Jan 8;12(1):29–41.
   PubMed Web of Science ®Google Scholar
• Kim H, Park HJ, Choi H, et al. Modeling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids. Stem Cell Reports. 2019 Mar 5;12(3):518–531.
   PubMed Web of Science ®Google Scholar
• Smits LM, Reinhardt L, Reinhardt P, et al. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 2019;5:5.
   PubMed Web of Science ®Google Scholar
• Chen ZC, Zhang W, Chua LL, et al. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci Signal. 2017 July 18;10:488.
   Web of Science ®Google Scholar
• Burbulla LF, Song P, Mazzulli JR, et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science. 2017 Sep 22;357(6357):1255–1261.
   PubMed Web of Science ®Google Scholar
• Seibler P, Graziotto J, Jeong H, et al. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci. 2011 Apr 20;31(16):5970–5976.
   PubMed Web of Science ®Google Scholar
• Devine MJ, Ryten M, Vodicka P, et al. Parkinson’s disease induced pluripotent stem cells with triplication of the alpha-synuclein locus. Nat Commun. 2011 Aug;23(2):440.
   Web of Science ®Google Scholar
• Mittal S, Bjornevik K, Im DS, et al. beta2-adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson’s disease. Science. 2017 Sep 1;357(6354):891–898.
   PubMed Web of Science ®Google Scholar
• Kouroupi G, Taoufik E, Vlachos IS, et al. Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease. Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3679–E3688.
   PubMed Web of Science ®Google Scholar
• Lashley T, Rohrer JD, Mead S, et al. Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations. Neuropathol Appl Neurobiol. 2015 Dec;41(7):858–881.
   PubMed Web of Science ®Google Scholar
• Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015 Oct 24;386(10004):1672–1682.
   PubMed Web of Science ®Google Scholar
• Burrell JR, Halliday GM, Kril JJ, et al. The frontotemporal dementia-motor neuron disease continuum. Lancet. 2016 Aug 27;388(10047):919–931.
   PubMed Web of Science ®Google Scholar
• Iovino M, Agathou S, Gonzalez-Rueda A, et al. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain. 2015 Nov;138(Pt 11):3345–3359.
   PubMed Web of Science ®Google Scholar
• Ehrlich M, Hallmann AL, Reinhardt P, et al. Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports. 2015 July 14;5(1):83–96.
   PubMed Web of Science ®Google Scholar
• Seo J, Kritskiy O, Watson LA, et al. Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J Neurosci. 2017 Oct 11;37(41):9917–9924.
   PubMed Web of Science ®Google Scholar
• Shi Y, Lin S, Staats KA, et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018 Mar;24(3):313–325.
   PubMed Web of Science ®Google Scholar
• Silva MC, Cheng C, Mair W, et al. Human iPSC-derived neuronal model of tau-A152T frontotemporal dementia reveals tau-mediated mechanisms of neuronal vulnerability. Stem Cell Reports. 2016 Sep 13;7(3):325–340.
   PubMed Web of Science ®Google Scholar
• Wang C, Christin JR, Oktay MH, et al. Lineage-biased stem cells maintain estrogen-receptor-positive and -negative mouse mammary luminal lineages. Cell Rep. 2017 Mar 21;18(12):2825–2835.
   PubMed Web of Science ®Google Scholar
• Lee WC, Almeida S, Prudencio M, et al. Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet. 2014 Mar 15;23(6):1467–1478.
   PubMed Web of Science ®Google Scholar
• Holler CJ, Taylor G, McEachin ZT, et al. Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Mol Neurodegener. 2016 June 24;11(1):46.
   PubMed Web of Science ®Google Scholar
• Chen H, Qian K, Du Z, et al. Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell. 2014 June 5;14(6):796–809.
   PubMed Web of Science ®Google Scholar
• Kiskinis E, Sandoe J, Williams LA, et al. Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell. 2014 June 5;14(6):781–795.
   PubMed Web of Science ®Google Scholar
• Wainger BJ, Kiskinis E, Mellin C, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1–11.
   PubMed Web of Science ®Google Scholar
• Sellier C, Campanari ML, Julie Corbier C, et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016 June 15;35(12):1276–1297.
   PubMed Web of Science ®Google Scholar
• Sivadasan R, Hornburg D, Drepper C, et al. C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci. 2016 Dec;19(12):1610–1618.
   PubMed Web of Science ®Google Scholar
• Webster CP, Smith EF, Bauer CS, et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. Embo J. 2016 Aug 1;35(15):1656–1676.
   PubMed Web of Science ®Google Scholar
• Wang W, Wang L, Lu J, et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med. 2016 Aug;22(8):869–878.
   PubMed Web of Science ®Google Scholar
• Marrone L, Poser I, Casci I, et al. Isogenic FUS-eGFP iPSC reporter lines enable quantification of FUS stress granule pathology that is rescued by drugs inducing autophagy. Stem Cell Reports. 2018 Feb 13;10(2):375–389.
   PubMed Web of Science ®Google Scholar
• Imamura K, Izumi Y, Watanabe A, et al. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med. 2017 May 24;9:391.
   Web of Science ®Google Scholar
• Okano H, Yasuda D, Fujimori K, et al. Ropinirole, a new ALS drug candidate developed using iPSCs. Trends Pharmacol Sci. 2020 Feb;41(2):99–109.
   PubMed Web of Science ®Google Scholar
• The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993 Mar 26;72(6): 971–983.
   PubMed Web of Science ®Google Scholar
• Caron NS, Dorsey ER, Hayden MR. Therapeutic approaches to Huntington disease: from the bench to the clinic. Nat Rev Drug Discov. 2018 Oct;17(10):729–750.
   PubMed Web of Science ®Google Scholar
• Consortium H. Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell. 2012 Aug 3;11(2):264–278.
   PubMed Web of Science ®Google Scholar
• Zhang N, Bailus BJ, Ring KL, et al. iPSC-based drug screening for Huntington’s disease. Brain Res. 2016 May 1;1638(Pt A):42–56.
   PubMed Web of Science ®Google Scholar
• Xu X, Tay Y, Sim B, et al. Reversal of phenotypic abnormalities by CRISPR/Cas9-mediated gene correction in Huntington disease patient-derived induced pluripotent stem cells. Stem Cell Reports. 2017 Mar 14;8(3):619–633.
   PubMed Web of Science ®Google Scholar
• Dickey AS, Sanchez DN, Arreola M, et al. PPARdelta activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med. 2017 Dec 6;9:419.
   Web of Science ®Google Scholar
• Consortium HDi. Developmental alterations in Huntington’s disease neural cells and pharmacological rescue in cells and mice. Nat Neurosci. 2017 May;20(5):648–660.
   PubMed Web of Science ®Google Scholar
• Victor MB, Richner M, Olsen HE, et al. Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat Neurosci. 2018 Mar;21(3):341–352.
   PubMed Web of Science ®Google Scholar
• Roessler R, Smallwood SA, Veenvliet JV, et al. Detailed analysis of the genetic and epigenetic signatures of iPSC-derived mesodiencephalic dopaminergic neurons. Stem Cell Reports. 2014 Apr 8;2(4):520–533.
   PubMed Web of Science ®Google Scholar
• Mertens J, Reid D, Lau S, et al. Aging in a dish: iPSC-derived and directly induced neurons for studying brain aging and age-related neurodegenerative diseases. Annu Rev Genet. 2018 Nov;23(52):271–293.
   Web of Science ®Google Scholar
• Schlaeger TM, Daheron L, Brickler TR, et al. A comparison of non-integrating reprogramming methods. Nat Biotechnol. 2015 Jan;33(1):58–63.
   PubMed Web of Science ®Google Scholar
• Kilpinen H, Goncalves A, Leha A, et al. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. 2017 June 15;546(7658):370–375.
   PubMed Web of Science ®Google Scholar
• Vincent F, Loria P, Pregel M, et al. Developing predictive assays: the phenotypic screening “rule of 3”. Sci Transl Med. 2015 June 24;7(293):293ps15.
   PubMed Web of Science ®Google Scholar
• Kimura J, Shimizu K, Kajima K, et al. Nobiletin reduces intracellular and extracellular beta-amyloid in iPS cell-derived Alzheimer’s disease model neurons. Biol Pharm Bull. 2018;41(4):451–457.
   PubMed Web of Science ®Google Scholar
• Almeida S, Gao F, Coppola G, et al. Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients. Neurobiol Aging. 2016 June;42:35–40.
   PubMed Web of Science ®Google Scholar
• Osborn TM, Beagan J, Isacson O. Increased motor neuron resilience by small molecule compounds that regulate IGF-II expression. Neurobiol Dis. 2018 Feb;110:218–230.
   PubMed Web of Science ®Google Scholar