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

被引：26

作者：

Banerjee, Poulomi ^{[1
,2
,3
]}

Mehta, Arpan R. ^{[2
,4
]}

Nirujogi, Raja S. ^{[5
]}

Cooper, James ^{[1
,2
,3
]}

James, Owen G. ^{[1
,2
,3
]}

Nanda, Jyoti ^{[1
,2
,3
]}

Longden, James ^{[1
,2
]}

Burr, Karen ^{[1
,2
,3
]}

McDade, Karina ^{[1
,2
,6
,7
]}

Salzinger, Andrea ^{[1
,2
,3
]}

Paza, Evdokia ^{[1
,2
]}

Newton, Judith ^{[3
,4
]}

Story, David ^{[1
,2
,3
]}

Pal, Suvankar ^{[2
,3
,4
]}

Smith, Colin ^{[2
,3
,6
,7
]}

Alessi, Dario R. ^{[5
]}

Selvaraj, Bhuvaneish T. ^{[1
,2
,3
]}

Priller, Josef ^{[1
,2
,8
,9
]}

Chandran, Siddharthan ^{[1
,2
,3
,4
]}

机构：

[1] Univ Edinburgh, UK Dementia Res Inst, Edinburgh bioQuarter, Chancellors Bldg,49 Little France Crescent, Edinburgh EH16 4SB, Scotland

[2] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Scotland

[3] Univ Edinburgh, Euan MacDonald Ctr MND Res, Edinburgh EH16 4SB, Scotland

[4] Univ Edinburgh, Anne Rowling Regenerat Neurol Clin, Edinburgh EH16 4SB, Scotland

[5] Univ Dundee, Sch Life Sci, Med Res Council MRC, Prot PhosphorylatUbiquitylat Unit, Dow St, Dundee DD1 5EH, Scotland

[6] Univ Edinburgh, Acad Dept Neuropathol, Edinburgh Brain Bank, Edinburgh, Scotland

[7] Univ Edinburgh, Edinburgh Pathol, Edinburgh, Scotland

[8] Tech Univ Munich, Sch Med, Dept Psychiat & Psychotherapy, Ismaninger Str 22, D-81675 Munich, Germany

[9] Neuropsychiatry, Charite Univ Med Berlin & DZNE, Charite pl 1, D-10117 Berlin, Germany

来源：

SCIENCE ADVANCES | 2023年 / 9卷 / 16期

基金：

英国医学研究理事会;

关键词：

INFLAMMASOME ACTIVATION; COMPUTATIONAL PLATFORM; NLRP3; INFLAMMASOME; C9ORF72; ALS; RNA; FTD; TOXICITY; COMPLEX;

D O I：

10.1126/sciadv.abq0651

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Although microglial activation is widely found in amyotrophic lateral sclerosis (ALS) and frontotemporal demen-tia (FTD), the underlying mechanism(s) are poorly understood. Here, using human-induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harboring the most common ALS/FTD mutation (C9orf72, mC9-MG), gene-corrected isogenic controls (isoC9-MG), and C9orf72 knockout hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated immune response upon stimulation with lipopolysaccharide. Analysis of the C9ORF72 interactome revealed that C9ORF72 interacts with regulators of autophagy and functional studies showed impaired initiation of autophagy in mC9-MG and C9KO-MG. Coculture studies with motor neurons (MNs) demonstrated that the autophagy deficit in mC9-MG drives increased vulnerability of mC9-MNs to excitotoxic stimulus. Pharmacological activation of autophagy amelio-rated both cell-autonomous functional deficits in hiPSC-MG and MN death in MG-MN coculture. Together, these findings reveal an important role for C9ORF72 in regulating immune homeostasis and identify dysregulation in myeloid cells as a contributor to neurodegeneration in ALS/FTD.

引用

页数：21

共 73 条

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