619
Views
13
CrossRef citations to date
0
Altmetric
Review

Cell death assays for neurodegenerative disease drug discovery

, &
Pages 901-913 | Received 21 Feb 2019, Accepted 22 May 2019, Published online: 10 Jun 2019

References

  • Heemels MT. Neurodegenerative diseases. Nature. 2016 Nov 10;539(7628):179.
  • Varma H, Lo DC, Stockwell B. High throughput screening for neurodegeneration and complex disease phenotypes. Comb Chem High Throughput Screen. 2008 Mar 01;11(3):238–248.
  • Kepp O, Galluzzi L, Lipinski M, et al. Cell death assays for drug discovery. Nat Rev Drug Discov. 2011 Mar;10(3):221–237.
  • Galluzzi L, Joza N, Tasdemir E, et al. No death without life: vital functions of apoptotic effectors. Cell Death Differ. 2008 Jul;15(7):1113–1123.
  • Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018 Mar;25(3):486–541.
  • Cobb MM, Ravisankar A, Skibinski G, et al. iPS cells in the study of PD molecular pathogenesis. Cell Tissue Res. 2017 Dec 12;373(1):61–77.
  • Haston KM, Finkbeiner S. Clinical trials in a dish: the potential of pluripotent stem cells to develop therapies for neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 2016 Jan 06;56(1):489–510.
  • Dj C, Zunino G, Jl B, et al. Phenotypic screening with primary neurons to identify drug targets for regeneration and degeneration. Mol Cell Neurosci. 2017 Apr;80:161–169.
  • Sherman SP, Bang AG. High-throughput screen for compounds that modulate neurite growth of human induced pluripotent stem cell-derived neurons. Dis Model Mech. 2018 Jan 11;11(2):dmm031906.
  • 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.
  • Palop JJ, Chin J, Mucke L. A network dysfunction perspective on neurodegenerative diseases. Nature. 2006 Oct 19;443(7113):768–773.
  • Kanai K, Kuwabara S, Misawa S, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006 Feb 08;129(4):953–962.
  • Kanai K, Shibuya K, Sato Y, et al. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 May 07;83(7):734–738.
  • Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013 Sep 01;70(9):1158.
  • Fosque BF, Sun Y, Dana H, et al. Labeling of active neural circuits in vivo with designed calcium integrators. Science. (New York, NY). 2015 Feb 12;347(6223):755–760.
  • Hochbaum DR, Zhao Y, Farhi SL, et al. All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat Methods. 2014 Aug;11(8):825–833.
  • Mz L, Mj S. Genetically encoded indicators of neuronal activity. Nat Neurosci. 2016 Aug 26;19(9):1142–1153.
  • Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2012 Aug 06;109(42):E2895–E903.
  • Wainger BJ, Kiskinis E, Mellin C, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr;7(1):1–11.
  • NIH. Levetiracetam for Alzheimer’s disease-associated network hyperexcitability (LEV-AD). 2013 July 19 [cited 2018]. Available from: https://clinicaltrials.gov/ct2/show/NCT02002819.
  • NIH. An investigation of levetiracetam in Alzheimer’s disease (ILiAD). 2018; [cited 2018 Oct 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT03489044
  • ALZFORUM. AGB101. ALZFORUM; 2018.
  • NIH. Clinical trial of ezogabine (retigabine) in ALS subjects. [cited 2018 Sep 27]; Available from: https://clinicaltrials.gov/ct2/show/NCT02450552
  • Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017 May 1;10(5):499–502.
  • Lee MK, Stirling W, Xu Y, et al. Human alpha-synuclein-harboring familial Parkinson’s disease-linked ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968–8973.
  • Xu YF, Zhang YJ, Lin WL, et al. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener. 2011 Oct 26;6:73.
  • Gotz J, Streffer JR, David D, et al. Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry. 2004 Jul;9(7):664–683.
  • Busche MA. In vivo two-photon calcium imaging of hippocampal neurons in Alzheimer mouse models. Methods Mol Biol. 2018;1750:341–351.
  • Barmada SJ, Skibinski G, Korb E, et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci. 2010 Jan 13;30(2):639–649.
  • Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004 Oct;431(7010):805–810.
  • Tsvetkov AS, Miller J, Arrasate M, et al. A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A. 2010 Sep 10;107(39):16982–16987.
  • Tsvetkov AS, Arrasate M, Barmada S, et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 2013 Jul 21;9(9):586–592.
  • Skibinski G, Hwang V, Ando DM, et al. Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis. Proc Natl Acad Sci U S A. 2016 Dec 27;114(5):1165–1170.
  • Barmada SJ, Serio A, Arjun A, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014 Aug;10(8):677–685.
  • Wang JKT, Portbury S, Thomas MB, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10461–10466.
  • Reinhart PH, Kaltenbach LS, Essrich C, et al. Identification of anti-inflammatory targets for Huntington’s disease using a brain slice-based screening assay. Neurobiol Dis. 2011 Jul;43(1):248–256.
  • Mewes A, Franke H, Singer D. Organotypic brain slice cultures of adult transgenic P301S mice–a model for tauopathy studies. PloS One. 2012;7(9):e45017.
  • Schommer J, Schrag M, Nackenoff A, et al. Method for organotypic tissue culture in the aged animal. MethodsX. 2017;4:166–171.
  • Shi Y, Inoue H, Wu JC, et al. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2016 Dec 16;16(2):115–130.
  • Imamura K, Sahara N, Kanaan NM, et al. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons. Sci Rep. 2016 Oct 10;6(1).
  • Serio A, Bilican B, Barmada SJ, et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4697–4702.
  • Fernandez-Santiago R, Carballo-Carbajal I, Castellano G, et al. Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. EMBO Mol Med. 2015 Dec;7(12):1529–1546.
  • 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 Feb 05;21(3):341–352.
  • Hoekstra SD, Stringer S, Heine VM, et al. Genetically-informed patient selection for iPSC studies of complex diseases may aid in reducing cellular heterogeneity. Front Cell Neurosci. 2017;11:164.
  • Jo J, Xiao Y, Sun AX, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016 Aug;19(2):248–257.
  • Birey F, Andersen J, Makinson CD, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017 Apr 26;545(7652):54–59.
  • Jorfi M, D’Avanzo C, Tanzi RE, et al. Human neurospheroid arrays for in vitro studies of Alzheimer’s disease. Sci Rep. 2018 Feb 05;8(1):2450.
  • Lee CT, Bendriem RM, Wu WW, et al. 3D brain organoids derived from pluripotent stem cells: promising experimental models for brain development and neurodegenerative disorders. J Biomed Sci. 2017 Aug 20;24(1):59.
  • Jorfi M, D’Avanzo C, Tanzi RE, et al. Human neurospheroid arrays for in vitro studies of Alzheimer’s Disease. Sci Rep. 2018 Feb 5;8(1):2450.
  • Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol. 2009 Aug;218(2):235–246.
  • Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012 Jun 13;342(3):619–630.
  • Pasca SP. Assembling human brain organoids. Science. (New York, NY). 2019 Jan 11;363(6423):126–127.
  • Wevers NR, van Vught R, Wilschut KJ, et al. High-throughput compound evaluation on 3D networks of neurons and glia in a microfluidic platform. Sci Rep. 2016 Dec;6(1):38856.
  • Li L, Zhou Q, Voss TC, et al. High-throughput imaging: focusing in on drug discovery in 3D. Methods. 2016 Mar; 96:97–102.
  • Gavrieli Y. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov 01;119(3):493–501.
  • Xu X, Lei Y, Luo J, et al. Prevention of beta-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of cyclin-dependent kinases and associated cell cycle events. Stem Cell Res. 2013 Mar;10(2):213–227.
  • Kolaja K. Stem cells and stem cell-derived tissues and their use in safety assessment. J Biol Chem. 2013 Dec 20;289(8):4555–4561.
  • Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017 Jan 20;18(2):101–113.
  • Rodrigue KM, Rieck JR, Kennedy KM, et al. Risk factors for beta-amyloid deposition in healthy aging: vascular and genetic effects. JAMA Neurol. 2013 May;70(5):600–606.
  • Thornberry NA. Caspases: enemies within. Science. (New York, NY). 1998 Aug 28;281(5381):1312–1316.
  • Tyas L, Brophy VA, Pope A, et al. Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep. 2000. 09; 1(3):266–270.
  • Gelles JD, Chipuk JE. Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging. Cell Death Dis. 2016 Dec 1;7(12):e2493.
  • Maiuri MC, Zalckvar E, Kimchi A, et al. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007 Sep;8(9):741–752.
  • Gorman AM. Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med. 2008 Dec;12(6a):2263–2280.
  • Imamura H, Nhat KP, Togawa H, et al. Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators. Proc Natl Acad Sci USA. 2009 Sep 15;106(37):15651–15656.
  • Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent parkin for mitophagy. J Cell Biol. 2010 Apr 19;189(2):211–221.
  • Narendra D, Walker JE, Youle R. Mitochondrial quality control mediated by PINK1 and parkin: links to parkinsonism. Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):a011338–a38.
  • Berridge MV, Herst PM, Tan AS. Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Annu Rev. 2005;11:127–152.
  • Pei Y, Peng J, Behl M, et al. Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes. Brain Res. 2016 May 1;1638(PtA):57–73.
  • Little D, Luft C, Mosaku O, et al. A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA. Sci Rep. 2018 Jun 13;8(1):9033.
  • Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. (New York, NY). 2012 Aug 30;337(6098):1062–1065.
  • Zamzami N. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med. 1995 Aug 01;182(2):367–377.
  • Wang JT, Medress ZA, Barres BA. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol. 2012 Jan 9;196(1):7–18.
  • Raff MC, Whitmore AV, Finn JT. Axonal self-destruction and neurodegeneration. Science. (New York, NY). 2002 May 3;296(5569):868–871.
  • Al-Ali H, Beckerman SR, Bixby JL, et al. In vitro models of axon regeneration. Exp Neurol. 2017 Jan;287(Pt 3):423–434.
  • Al-Ali H, Schurer SC, Lemmon VP, et al. Chemical interrogation of the neuronal kinome using a primary cell-based screening assay. ACS Chem Biol. 2013 May 17;8(5):1027–1036.
  • Al-Ali H, Lee DH, Danzi MC, et al. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth. ACS Chem Biol. 2015 Aug 21;10(8):1939–1951.
  • Al-Ali H, Debevec G, Santos RG, et al. Scaffold ranking and positional scanning identify novel neurite outgrowth promoters with nanomolar potency. ACS Med Chem Lett. 2018 Sep 24;9(10):1057–1062.
  • Whitlon DS, Grover M, Dunne SF, et al. Novel high content screen detects compounds that promote neurite regeneration from cochlear spiral ganglion neurons. Sci Rep. 2015 Nov 02;5(1):15960.
  • Rudhard Y, Sengupta Ghosh A, Lippert B, et al. Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening. J Neurosci. 2015 Feb 18;35(7):2927–2941.
  • Ehrlich M, Hallmann A-L, 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 Jul;5(1):83–96.
  • Egawa N, Kitaoka S, Tsukita K, et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med. 2012 Aug 01;4(145):145ra04–45ra04.
  • Devlin AC, Burr K, Borooah S, et al. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun. 2015 Jan 12;6(1).
  • Shi Y, Lin S, Staats KA, et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018 Feb 05;24(3):313–325.
  • Kiskinis E, Kralj JM, Zou P, et al. All-optical electrophysiology for high-throughput functional characterization of a human iPSC-derived motor neuron model of ALS. Stem Cell Reports. 2018 Jun 5;10(6):1991–2004.
  • TiL L, Atchison WD. Application of single-cell microfluorimetry to neurotoxicology assays. Curr Protoc Toxicol. 2009 Nov;42(1):15.
  • Virdee JK, Saro G, Fouillet A, et al. A high-throughput model for investigating neuronal function and synaptic transmission in cultured neuronal networks. Sci Rep. 2017 Nov 3;7(1):14498.
  • Bassett JJ, Monteith GR. Genetically encoded calcium indicators as probes to assess the role of calcium channels in disease and for high-throughput drug discovery. Adv Pharmacol. 2017;79:141–171.
  • Hempel CM, Sivula M, Levenson JM, et al. A system for performing high throughput assays of synaptic function. PloS One. 2011;6(10):e25999.
  • Piatkevich KD, Jung EE, Straub C, et al. A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. Nat Chem Biol. 2018 Apr;14(4):352–360.
  • Bae JS, Simon NG, Menon P, et al. The puzzling case of hyperexcitability in amyotrophic lateral sclerosis. J Clin Neurol. 2013 Apr;9(2):65–74.
  • Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014 Apr;115:157–188.
  • Arrasate M, Finkbeiner S. Automated microscope system for determining factors that predict neuronal fate. Proc Natl Acad Sci U S A. 2005 Feb 28;102(10):3840–3845.
  • Finkbeiner S, Frumkin M, Kassner PD. Cell-based screening: extracting meaning from complex data. Neuron. 2015 Apr;86(1):160–174.
  • Miller J, Arrasate M, Brooks E, et al. Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat Chem Biol. 2011 Oct 30;7(12):925–934.
  • Shaby BA, Skibinski G, Ando M, et al. A three-groups model for high-throughput survival screens. Biometrics. 2016 Sep;72(3):936–944.
  • Linsley JW, Tripathi A, Epstein I, et al. Automated four-dimensional long term imaging enables single cell tracking within organotypic brain slices to study neurodevelopment and degeneration. Commun Biol. 2019 May 01;2(1):155.
  • Miller J, Arrasate M, Shaby BA, et al. Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington’s disease molecular pathogenesis. J Neurosci. 2010 Aug 04;30(31):10541–10550.
  • Christiansen EM, Yang SJ, Ando DM, et al. In silico labeling: predicting fluorescent labels in unlabeled images. Cell. 2018 Apr 19;173(3):792–803.e19.
  • Eglen RM, Reisine T. Human iPS cell-derived patient tissues and 3D cell culture part 1: target identification and lead optimization. SLAS Technol. 2018 Oct 04;24(1):3–17.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.