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SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease


Zhu, Caihong; Li, Bei; Frontzek, Karl; Liu, Yingjun; Aguzzi, Adriano (2019). SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. Journal of Experimental Medicine:jem.20171885.

Abstract

SARM1 (sterile α and HEAT/armadillo motif–containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.

Abstract

SARM1 (sterile α and HEAT/armadillo motif–containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Uncontrolled Keywords:Immunology, Immunology and Allergy
Language:English
Date:6 March 2019
Deposited On:13 Mar 2019 13:34
Last Modified:29 Jul 2020 10:25
Publisher:Rockefeller University Press
ISSN:0022-1007
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1084/jem.20171885
PubMed ID:30842236
Project Information:
  • : FunderFP7
  • : Grant ID250356
  • : Project TitlePRIONS - The prion protein in health and disease
  • : FunderGELU Foundation
  • : Grant ID
  • : Project TitleCRYSTAL & HITS
  • : FunderSNSF
  • : Grant ID310030B_160329
  • : Project TitleThe prion protein in health and disease
  • : FunderSNSF
  • : Grant IDCRSII3_147660
  • : Project TitleCalcium imaging of cellular and circuit dysfunctions in neurodegeneration
  • : FunderCRPP UZH
  • : Grant ID
  • : Project TitleSmall RNAs
  • : FunderCRPP UZH
  • : Grant ID
  • : Project TitleHHLD
  • : FunderTheodor und Ida Herzog-Egli Foundation
  • : Grant ID
  • : Project Title
  • : FunderSystemsX.ch
  • : Grant ID2014/260
  • : Project TitlePrionX
  • : FunderSPHN
  • : Grant ID2017DRI17
  • : Project TitlePopulation-wide screens of the human immune repertoire: a reverse personalized-medicine approach

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