Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

Colombo, Emanuela; Cordiglieri, Chiara; Melli, Giorgia; Newcombe, Jia; Krumbholz, Markus; Parada, Luis F.; Medico, Enzo; Hohlfeld, Reinhard; Meinl, Edgar; Farina, Cinthia

doi:10.1083/jcb1966oia8

Cited by 24 publications

(68 citation statements)

References 48 publications

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“…Primary astrocyte cultures from C57BL/6 and Rai 2/2 mice were established from newborn mice (2 d old), as previously described (27). Purity was assessed by flow cytometry using Alexa-fluor 488-conjugated anti-GFAP mAb (clone GA5; eBioscience).…”

Section: Primary Astrocyte Culture Stimulation and Analysismentioning

confidence: 99%

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

Ulivieri

Savino

Luccarini

et al. 2016

The Journal of Immunology

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Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai−/− mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai+/+ mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis.

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Section: Primary Astrocyte Culture Stimulation and Analysismentioning

confidence: 99%

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

Ulivieri

Savino

Luccarini

et al. 2016

The Journal of Immunology

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“…Although BDNF-TrkB receptor mediated intracellular signaling is mainly regarded as a contributor to synaptic development and plasticity (48), this pathway has also been shown to play a role in neurodegeneration (49) and promote cell death in vitro (50,51). In addition, several studies have indicated a role of BDNF-TrkB receptor signaling in the development of epilepsy (52)(53)(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP

Poddar¹,

Rajagopal²,

Shuttleworth

et al. 2016

Journal of Biological Chemistry

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Excessive release of Zn 2؉ in the brain is implicated in the progression of acute brain injuries. Although several signaling cascades have been reported to be involved in Zn 2؉ -induced neurotoxicity, a potential contribution of tyrosine phosphatases in this process has not been well explored. Here we show that exposure to high concentrations of Zn 2؉ led to a progressive increase in phosphorylation of the striatal-enriched phosphatase (STEP), a component of the excitotoxic-signaling pathway that plays a role in neuroprotection. Zn 2؉ -mediated phosphorylation of STEP 61 at multiple sites (hyperphosphorylation) was induced by the up-regulation of brain-derived neurotropic factor (BDNF), tropomyosin receptor kinase (Trk) signaling, and activation of cAMP-dependent PKA (protein kinase A). Mutational studies further show that differential phosphorylation of STEP 61 at the PKA sites, Ser-160 and Ser-221 regulates the affinity of STEP 61 toward its substrates. Consistent with these findings we also show that BDNF/Trk/PKA mediated signaling is required for Zn 2؉ -induced phosphorylation of extracellular regulated kinase 2 (ERK2), a substrate of STEP that is involved in Zn 2؉ -dependent neurotoxicity. The strong correlation between the temporal profile of STEP 61 hyperphosphorylation and ERK2 phosphorylation indicates that loss of function of STEP 61 through phosphorylation is necessary for maintaining sustained ERK2 phosphorylation. This interpretation is further supported by the findings that deletion of the STEP gene led to a rapid and sustained increase in ERK2 phosphorylation within minutes of exposure to Zn 2؉ . The study provides further insight into the mechanisms of regulation of STEP 61 and also offers a molecular basis for the Zn 2؉ -induced sustained activation of ERK2.A growing body of evidence indicates that Zn 2ϩ , the second most abundant transition metal in the brain, is released at high concentrations during excitotoxic neurological conditions and can contribute to neuronal injury (1-7). The proposed mechanisms associated with Zn 2ϩ -dependent neurotoxicity include alteration of activity of a diverse group of post-synaptic receptors like ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 3 N-methyl-D-aspartic acid (NMDA), voltagegated calcium channels and neurotrophic receptors (7-12). Receptor activation in turn modulates the function of several intracellular kinases including protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (ERK MAPK), and the Src family of tyrosine kinases resulting in impaired energy production, excitability and oxidative stress (8,9,(13)(14)(15). However, the role of phosphatases in Zn 2ϩ -induced neurotoxicity is currently not well understood.The intracellular tyrosine phosphatase, STEP (striatalenriched tyrosine phosphatase, also known as PTPN5) is expressed exclusively in the central nervous system (16,17) and is emerging as a key regulator of neuronal survival and death. The STEP-family of PTPs includes both membrane-assoc...

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“…Many studies in models of MS support this idea [31]. Yet, it has also been found that BDNF signalling via TrkB on astrocytes may enhance nitric oxide production and neuro degeneration in experimental autoimmune encephalomyelitis [17]; therefore, the role of BDNF in inflammatory demyelinating disease in not fully understood.…”

Section: Journal Of Autoimmune Disorders Issn 2471-8513mentioning

confidence: 91%

“…BDNF has been postulated to be a potential therapy for reducing neurodegeneration in MS [16]. However, it has also been demonstrated that trkB signaling via BDNF on astrocytes promotes nitric oxide production and neurodegeneration [17]. Thus, enhanced BDNF levels may have both beneficial and detrimental effects in MS.…”

Section: Journal Of Autoimmune Disorders Issn 2471-8513mentioning

confidence: 99%

Analysis of miRNA in Normal Appearing White Matter to Identify Altered CNS Pathways in Multiple Sclerosis

Guerau-de-Arellano

Liu

Meisen

et al. 2015

J Autoimmune Disord

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Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

Cited by 24 publications

References 48 publications

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP

Analysis of miRNA in Normal Appearing White Matter to Identify Altered CNS Pathways in Multiple Sclerosis

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