A neuroprotective role for microglia in prion diseases

Zhu, Chuanbing; Herrmann, U.; Falsig, Jeppe; Абакумова, Ирина; Schwarz, Petra; Frauenknecht, Katrin; Aguzzi, Adriano

doi:10.1083/jcb.2134oia109

Cited by 22 publications

(39 citation statements)

References 20 publications

(28 reference statements)

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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

Self Cite

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“…Since IL‐34 is expressed at mRNA level in various tissues, this expression is expected to be changed under pathological conditions. Indeed, several studies have confirmed the enhancement of IL‐34 expression at mRNA and protein levels in the context of various diseases including autoimmune disorders, inflammation, infections, metabolic diseases, neurological disorders, and cancer . At the cellular level, IL‐34‐producing cells include synovial fibroblasts, immune cells, epithelial cells, endothelial cells, adipocytes, and cancer cells.…”

Section: Il‐34 Biologymentioning

confidence: 95%

“…have found in a murine model of prion disease that the deficiency of microglia in Il34 −/− mice resulted in more astrogliosis and a significant acceleration of prion disease progression. The scarcity of microglia at early stages of prion infection or poorly understood defects in microglial functions was suggested to play a role in determining disease progression . In this regard, it is of great interest to examine the expression levels of IL‐34 in the context of prion diseases.…”

Section: Pathological Roles Of Il‐34mentioning

confidence: 99%

Interleukin-34, a comprehensive review

Baghdadi

Umeyama

Hama

et al. 2018

Journal of Leukocyte Biology

106

120

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IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish, amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34 belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consensus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ζ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions, changes in IL-34 expression-increased or decreased-are involved in disease pathogenesis and correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been introduced as a newcomer to the big family of interleukins with specific physiological functions, critical pathological roles, and promising clinical applications in disease diagnosis and treatment. In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological characteristics, and discussing the importance of IL-34 signaling network in health and disease.

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“…Microglia alterations could promote neuronal dysfunction in various neurodegenerative disorders (Perry et al, 2010;Bosch & Kielian, 2015). In contrast, microglia play beneficial roles in prion-induced neurodegeneration (Zhu et al, 2016) or amyotrophic lateral sclerosis (Spiller et al, 2018). A unique microglia type, the disease-associated microglia (DAM), has been recently associated with restricting development of Alzheimer 0 s disease (Keren-Shaul et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

et al. 2018

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Neuropathic lysosomal storage disorders ( LSD s) present with activated pro‐inflammatory microglia. However, anti‐inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann–Pick disease type A ( NPA ). We establish that an NPA patient and the acid sphingomyelinase knockout ( ASM ko) mouse model show amoeboid microglia in neurodegeneration‐prone areas. In vivo microglia ablation worsens disease progression in ASM ko mice. We demonstrate the coexistence of different microglia phenotypes in ASM ko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build‐up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASM ko mice. Similar microglia phenotypes occur in a Niemann–Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSD s and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSD s and other demyelinating diseases.

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A neuroprotective role for microglia in prion diseases

Cited by 22 publications

References 20 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

Interleukin-34, a comprehensive review

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

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