Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schätzl, T.
eIF2a-P mediated translational repression induces neurotoxic A1 reactivity in astrocytes via NF¿B and its implications in prion disease
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2018. pp. 71
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Haybäck Johannes
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- Abstract:
- There are an increasing number of neurodegenerative disorders which are recognized to result from aggregation of misfolded proteins. Understanding cellular mechanisms of neurodegeneration is of fundamental scientific importance as neurodegenerative diseases represent one of the biggest health problems in our aging society, and uncovering molecular mechanisms of general validity is fundamental for developing rational therapies. Dysregulated activation of the unfolded protein response (UPR) is thought to drive the pathology of many neurodegenerative diseases, particularly due to transient shutdown of translation, mediated by the PERK-eIF2¿ branch. Various interconnections between UPR and the NF¿B pathway, a transcriptional master regulator for pro-inflammatory signaling, have been described in different cell lines. Additional evidence suggests that the recently defined neurotoxic A1 reactive astrogliosis is induced by astroglial NF¿B and has a detrimental impact in several neurodegenerative diseases. As the role of astrocytic UPR activation and reactivity which accompanies neuronal pathology is not well understood, we analyzed A1 reactivity and NF¿B signaling in murine prion disease and explored the connection of UPR mediated translational shutdown, NF¿B and A1 reactivity in primary astrocytes. To characterize the role of neurotoxic A1 reactivity in prion disease, complement component 3 levels, a marker for A1 reactivity, were analyzed in mouse hippocampi during disease progression using immunofluorescence assay. We observed increased A1 reactivity in astrocytes of prion infected mice. In addition, we demonstrated that prion disease caused increased nuclear NF¿B and decreased whole-cell I¿B¿ levels during disease progression. Moreover, we show that pharmacological UPR stressors or genetic PERK-branch manipulation activated the NF¿B pathway through translational repression mediated I¿B¿ decrease in primary cultured astrocytes, and led to expression of A1-reactive markers. Neurotoxicity in genetically PERK-branch activated primary astrocytes was evident as reduced maintenance of synapses in co-cultured primary hippocampal neurons. In conclusion, these results support the concept that dysregulated eIF2¿-P-mediated translational repression of astrocytes can have detrimental effects on neurons via NF¿B signaling, thereby inducing neurotoxic A1 reactivity. As targeting the neuronal UPR in neurodegeneration is a robust treatment, we propose that inhibiting or reversing dysregulated astrocytic UPR leads to synergistic and neuroprotective effects by partially preventing their neurotoxic A1 reactive state.