Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

Sakai, Keiko; Hasebe, Rie; Takahashi, Yusuke; Song, Chang‐Hyun; Suzuki, Akio; Yamasaki, Takahiro; Horiuchi, Motohiro

doi:10.1128/jvi.02072-13

Cited by 36 publications

(30 citation statements)

References 56 publications

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“…These results indicate that SARM1 deficiency accelerates prion progression, and suggest a possible effect of SARM1 haploinsufficiency, implying that SARM1 instead plays a neuroprotective role in prion pathogenesis. The effect of SARM1 deficiency on prion progression was moderate, but it was statistically significant and its magnitude is comparable to that seen in other genetically-modified animal models or upon pharmacological treatments (Goniotaki et al, 2017;Grizenkova et al, 2014;Herrmann et al, 2015;Sakai et al, 2013;Sorce et al, 2014;Zhu et al, 2016).…”

Section: Sarm1 Deficiency Resulted In Accelerated Prion Progressionsupporting

confidence: 57%

SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease

Zhu

Frontzek

et al. 2018

Preprint

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Condensed title: SARM1 deficiency accelerates prion diseasesAbbreviations: CNS, central nervous system; dpi, days post inoculation; MyD88, myeloid differentiation primary response gene 88; NBH, non-infectious brain homogenates; PK, proteinase K; qRT-PCR, quantitative real-time PCR; RML6, Rocky Mountain Laboratories scrapie strain passage 6; SARM1, sterile α and HEAT/armadillo motifs containing protein; XAF1, X-linked inhibitor of apoptosis-associated factor 1. | P a g eAbstract SARM1 (sterile α and HEAT/armadillo motifs 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. Wholetranscriptome 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 proapoptotic caspases and neuronal death were enhanced in prion-infected SARM1 -/mice. These results point to an unexpected function of SARM1 as a regulator of prioninduced neurodegeneration, and suggest that XAF1 might constitute a therapeutic target in prion disease.

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Section: Sarm1 Deficiency Resulted In Accelerated Prion Progressionsupporting

confidence: 57%

SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease

Zhu

Frontzek

et al. 2018

Preprint

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“…In contrast, expression of the proinflammatory cytokine IL-1β in microglia appeared to be decreased in Cd14 -/-mice in the early stage of prion infection. These results imply that CD14 plays a detrimental role in prion pathogenesis by promoting proinflammatory responses and/or inhibiting antiinflammatory responses in the brain (56,57).…”

Section: Microglia-related Transducers In Prion Diseasesmentioning

confidence: 87%

Microglia in prion diseases

Aguzzi

Zhu

2017

Journal of Clinical Investigation

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“…Among the shared target genes, Cd14 is a glycosylphosphatidylinositol-anchored receptor known as a co-receptor for TLRs [65] and critical for Tlr2mediated macrophage activation [66]. Absence of Cd14 delays progression of prion diseases accompanied by increased microglial activation [67]. Inhibition of Csf1r decreases microglial proliferation and delays neuronal damage in prion disease [56].…”

Section: Discussionmentioning

confidence: 99%

Core transcriptional regulatory circuits in prion diseases

et al. 2020

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Complex diseases involve dynamic perturbations of pathophysiological processes during disease progression. Transcriptional programs underlying such perturbations are unknown in many diseases. Here, we present core transcriptional regulatory circuits underlying early and late perturbations in prion disease. We first identified cellular processes perturbed early and late using time-course gene expression data from three prion-infected mouse strains. We then built a transcriptional regulatory network (TRN) describing regulation of early and late processes. We found over-represented feed-forward loops (FFLs) comprising transcription factor (TF) pairs and target genes in the TRN. Using gene expression data of brain cell types, we further selected active FFLs where TF pairs and target genes were expressed in the same cell type and showed correlated temporal expression changes in the brain. We finally determined core transcriptional regulatory circuits by combining these active FFLs. These circuits provide insights into transcriptional programs for early and late pathophysiological processes in prion disease.

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Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

Cited by 36 publications

References 56 publications

SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease

SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease

Microglia in prion diseases

Core transcriptional regulatory circuits in prion diseases

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