Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration

Poulomi Banerjee; Arpan Mehta; Raja S Nirujogi; James Cooper; Owen Gwydion James; Jyoti Nanda; James Longden; Karen Burr; Karina McDade; Andrea Salzinger; Evdokia Paza; Judith Newton; David Story; Suvankar Pal; Colin Smith; Dario R Alessi; Bhuvaneish Thangaraj Selvaraj; Josef Priller; Siddharthan Chandran

doi:10.1126/sciadv.abq0651

Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration

Poulomi Banerjee, Arpan Mehta, Raja S Nirujogi, James Cooper, Owen Gwydion James, Jyoti Nanda, James Longden, Karen Burr, Karina McDade, Andrea Salzinger, Evdokia Paza, Judith Newton, David Story, Suvankar Pal, Colin Smith, Dario R Alessi, Bhuvaneish Thangaraj Selvaraj, Josef Priller, Siddharthan Chandran

Research output: Contribution to journal › Article › peer-review

Original language	English
Journal	Science Advances
DOIs	https://doi.org/10.1126/sciadv.abq0651
Publication status	Published - 21 Apr 2023

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Banerjee, P., Mehta, A., Nirujogi, R. S., Cooper, J., James, O. G., Nanda, J., Longden, J., Burr, K., McDade, K., Salzinger, A., Paza, E., Newton, J., Story, D., Pal, S., Smith, C., Alessi, D. R., Thangaraj Selvaraj, B., Priller, J., & Chandran, S. (2023). Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Science Advances. https://doi.org/10.1126/sciadv.abq0651

@article{95692ff62a494ecc8787a875062a7c52,

title = "Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration",

author = "Poulomi Banerjee and Arpan Mehta and Nirujogi, {Raja S} and James Cooper and James, {Owen Gwydion} and Jyoti Nanda and James Longden and Karen Burr and Karina McDade and Andrea Salzinger and Evdokia Paza and Judith Newton and David Story and Suvankar Pal and Colin Smith and Alessi, {Dario R} and {Thangaraj Selvaraj}, Bhuvaneish and Josef Priller and Siddharthan Chandran",

note = "Funding Information: Chandran laboratory is supported by a Medical Research Council grant (MR/L016400/1), the Euan MacDonald Centre for Motor Neurone Disease Research, the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer{\textquoteright}s Society, and Alzheimer{\textquoteright}s Research UK, and an MS Society Edinburgh Centre of Excellence award. J.P. is supported by a program grant from the UK DRI and by grants from the German Research Foundation (DFG SFB/TRR167 B07). A.R.M. was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). A.R.M. also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh. The creation of an EGFP-C9orf72 tagged human iPSC line and patient blood–derived experiments were supported by a seedcorn grants to A.R.M. and P.B., respectively, from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by University of St Andrews. B.T.S. is a Rowling-DRI Fellow. The D.R.A. laboratory is supported by the U.K. Medical Research Council (grant number MC_UU_00018/1). Funding Information: Acknowledgments:W ethankD.Scott(UniversityofNottingham)andR.Layfield(Universityof Nottingham)forsharingthemCherry-GFP-p62plasmid.W ealsothankP .Brown(Universityof Edinburgh)forgeneratingthelentiviralvectors.Flowcytometrydataweregeneratedwithinthe FlowCytometryandCellSortingFa cility inMRCCentreforRegenerativeMedicine.Someofthe illustrationsinthemanuscriptwerecreatedwithBioRender.com.Funding:Chandran laboratoryissupportedbyaMedicalResearchCouncilgrant(MR/L016400/1),theEuan MacDonaldCentreforMotorNeuroneDiseaseResearch,theUKDementiaResearchInstitute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer{\textquoteright}s Society, and Alzheimer{\textquoteright}s Research UK, and an MS Society Edinburgh Centre of Excellence award. J.P . is supportedbyaprogramgrantfromtheUKDRIandbygrantsfromtheGermanResearch Foundation(DFGSFB/TRR167B07).A.R.M.wasaLadyEdithW olfson ClinicalFellow,jointly fundedbytheMedicalResearchCouncil(MRC)andtheMotorNeuroneDiseaseAssociation (MR/R001162/1).A.R.M.alsoacknowledgessupportfromtheRo wling Scholarsscheme, administeredbytheAnneRowlingRegenerativeNeurologyClinic(ARRNC),Universityof Edinburgh.ThecreationofanEGFP-C9orf72taggedhumaniPSClineandpatientblood– derivedexperimentsweresupportedbyaseedcorngrantstoA.R.M.andP .B., respectively,from TheChiefScientistOfficeandtheRSMacdonaldCharitableTrustviatheScottishNeurological ResearchFund,administeredbyUniversityofStAndrews.B.T .S. isaRowling-DRIFellow.The D.R.A.labora tory issupportedbytheU.K.MedicalResearchCouncil(grantnumber MC_UU_00018/1).Authorcontributions:P .B.: Conceptualization,validation,investigation, visualization,methodology,writing—originaldraft,projectadministration,andwriting— review and editing. A.R.M.: Methodology, investigation, resources, and writing—reviewand editing.R.S.N.:Methodology,investiga tion, andwriting—reviewandediting.J.C.:Methodology and resources. O.G.J.: Methodology, software, and formal analysis. J.Na.: Investigation. J.L.: Methodology,software,andformalanalysis.K.B.:Resources.K.M.:Investigation.A.S.: Methodologyandinvestigation.E.P .: Investigation.J.Ne.:Resources(clinicalwork).D.S.: Resources(administr ativesupport).S.P .: Resources(recruitmentofpatientsviaARRNC).C.S.: Resources (postmortem samples), supervision, and writing—review and editing. D.R.A.: Methodology, validation, supervision, investigation, and writing—review and editing. B.T .S.: Conceptualisation,methodology,writing—reviewandediting,andprojectadministration.J.P .: Conceptualization, supervision, project administration, visualization, and writing—review and editing. S.C.: Conceptualization, resources, supervision, project administration, visualization, writing—original draft, writing—review and editing, and funding acquisition. Competing interests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataandmaterials availability:Alldataneededtoevaluatetheconclusionsinthepaperarepresentinthepaper and/ortheSupplementaryMaterials.CelllinescanbeprovidedbyS.C.,UniversityofEdinburgh, pending scientific reviewand acompleted material transferagreement. Requests forcell lines shouldbesubmittedtosiddharthan.chandran@ed.ac.uk.Rawdataanddatabasesearchresults forthemassspectrometryexperimentshav ebeenuploadedinonlineproteomicsidentification database ProteomeXchange PRIDE repository with a PRIDE dataset identifier number PXD032320. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = apr,

day = "21",

doi = "10.1126/sciadv.abq0651",

language = "English",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

}

Banerjee, P , Mehta, A, Nirujogi, RS, Cooper, J, James, OG, Nanda, J, Longden, J, Burr, K, McDade, K, Salzinger, A, Paza, E, Newton, J, Story, D , Pal, S , Smith, C, Alessi, DR, Thangaraj Selvaraj, B , Priller, J & Chandran, S 2023, 'Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration', Science Advances. https://doi.org/10.1126/sciadv.abq0651

TY - JOUR

T1 - Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration

AU - Banerjee, Poulomi

AU - Mehta, Arpan

AU - Nirujogi, Raja S

AU - Cooper, James

AU - James, Owen Gwydion

AU - Nanda, Jyoti

AU - Longden, James

AU - Burr, Karen

AU - McDade, Karina

AU - Salzinger, Andrea

AU - Paza, Evdokia

AU - Newton, Judith

AU - Story, David

AU - Pal, Suvankar

AU - Smith, Colin

AU - Alessi, Dario R

AU - Thangaraj Selvaraj, Bhuvaneish

AU - Priller, Josef

AU - Chandran, Siddharthan

N1 - Funding Information: Chandran laboratory is supported by a Medical Research Council grant (MR/L016400/1), the Euan MacDonald Centre for Motor Neurone Disease Research, the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer’s Society, and Alzheimer’s Research UK, and an MS Society Edinburgh Centre of Excellence award. J.P. is supported by a program grant from the UK DRI and by grants from the German Research Foundation (DFG SFB/TRR167 B07). A.R.M. was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). A.R.M. also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh. The creation of an EGFP-C9orf72 tagged human iPSC line and patient blood–derived experiments were supported by a seedcorn grants to A.R.M. and P.B., respectively, from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by University of St Andrews. B.T.S. is a Rowling-DRI Fellow. The D.R.A. laboratory is supported by the U.K. Medical Research Council (grant number MC_UU_00018/1). Funding Information: Acknowledgments:W ethankD.Scott(UniversityofNottingham)andR.Layfield(Universityof Nottingham)forsharingthemCherry-GFP-p62plasmid.W ealsothankP .Brown(Universityof Edinburgh)forgeneratingthelentiviralvectors.Flowcytometrydataweregeneratedwithinthe FlowCytometryandCellSortingFa cility inMRCCentreforRegenerativeMedicine.Someofthe illustrationsinthemanuscriptwerecreatedwithBioRender.com.Funding:Chandran laboratoryissupportedbyaMedicalResearchCouncilgrant(MR/L016400/1),theEuan MacDonaldCentreforMotorNeuroneDiseaseResearch,theUKDementiaResearchInstitute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer’s Society, and Alzheimer’s Research UK, and an MS Society Edinburgh Centre of Excellence award. J.P . is supportedbyaprogramgrantfromtheUKDRIandbygrantsfromtheGermanResearch Foundation(DFGSFB/TRR167B07).A.R.M.wasaLadyEdithW olfson ClinicalFellow,jointly fundedbytheMedicalResearchCouncil(MRC)andtheMotorNeuroneDiseaseAssociation (MR/R001162/1).A.R.M.alsoacknowledgessupportfromtheRo wling Scholarsscheme, administeredbytheAnneRowlingRegenerativeNeurologyClinic(ARRNC),Universityof Edinburgh.ThecreationofanEGFP-C9orf72taggedhumaniPSClineandpatientblood– derivedexperimentsweresupportedbyaseedcorngrantstoA.R.M.andP .B., respectively,from TheChiefScientistOfficeandtheRSMacdonaldCharitableTrustviatheScottishNeurological ResearchFund,administeredbyUniversityofStAndrews.B.T .S. isaRowling-DRIFellow.The D.R.A.labora tory issupportedbytheU.K.MedicalResearchCouncil(grantnumber MC_UU_00018/1).Authorcontributions:P .B.: Conceptualization,validation,investigation, visualization,methodology,writing—originaldraft,projectadministration,andwriting— review and editing. A.R.M.: Methodology, investigation, resources, and writing—reviewand editing.R.S.N.:Methodology,investiga tion, andwriting—reviewandediting.J.C.:Methodology and resources. O.G.J.: Methodology, software, and formal analysis. J.Na.: Investigation. J.L.: Methodology,software,andformalanalysis.K.B.:Resources.K.M.:Investigation.A.S.: Methodologyandinvestigation.E.P .: Investigation.J.Ne.:Resources(clinicalwork).D.S.: Resources(administr ativesupport).S.P .: Resources(recruitmentofpatientsviaARRNC).C.S.: Resources (postmortem samples), supervision, and writing—review and editing. D.R.A.: Methodology, validation, supervision, investigation, and writing—review and editing. B.T .S.: Conceptualisation,methodology,writing—reviewandediting,andprojectadministration.J.P .: Conceptualization, supervision, project administration, visualization, and writing—review and editing. S.C.: Conceptualization, resources, supervision, project administration, visualization, writing—original draft, writing—review and editing, and funding acquisition. Competing interests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataandmaterials availability:Alldataneededtoevaluatetheconclusionsinthepaperarepresentinthepaper and/ortheSupplementaryMaterials.CelllinescanbeprovidedbyS.C.,UniversityofEdinburgh, pending scientific reviewand acompleted material transferagreement. Requests forcell lines shouldbesubmittedtosiddharthan.chandran@ed.ac.uk.Rawdataanddatabasesearchresults forthemassspectrometryexperimentshav ebeenuploadedinonlineproteomicsidentification database ProteomeXchange PRIDE repository with a PRIDE dataset identifier number PXD032320. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved.

PY - 2023/4/21

Y1 - 2023/4/21

U2 - 10.1126/sciadv.abq0651

DO - 10.1126/sciadv.abq0651

M3 - Article

SN - 2375-2548

JO - Science Advances

JF - Science Advances

ER -