Unfolding the mystery of UPR in astrocytes

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Science Translational Medicine  29 Jan 2020:
Vol. 12, Issue 528, eaba2916
DOI: 10.1126/scitranslmed.aba2916


Activation of the unfolded protein response in astrocytes leads to a distinct reactive state detrimental to neuronal health in prion disease.

The accumulation of misfolded proteins is characteristic of several neurodegenerative diseases, leading to neuronal stress and activation of the unfolded protein response (UPR). Within neurons, the UPR is dependent on the phosphorylation of protein kinase R–like ER kinase (PERK) and its downstream target the eukaryotic initiation factor 2α (eIF2α), which ultimately reduces global protein synthesis, leading to neuronal loss.

Although the UPR in neurons has been well characterized, the astrocytic UPR in neurodegeneration remained unclear. Now, Smith et al. investigate the astrocytic UPR by treating primary astrocytes with the endoplasmic reticulum (ER) stressors thapsigargin (Tg) or tunicamycin (Tm). Their treatment promoted the phosphorylation of PERK and eIF2α. Characteristically to UPR, the downstream markers ATF4 and GADD34 were also found to be elevated together with a reduction in global protein synthesis. To assess the reactivity state of astrocytes, a panel of proinflammatory genes were measured identifying an increase in Cxcl10, Lcn2, Vim, and C3. The pharmacological inhibition or PERK or small interfering RNA targeting PERK expression reduced eIF2α-P and suppressed the expression of proinflammatory genes. To evaluate the role of UPR-activated astrocytes on neuronal health, primary hippocampal neurons were incubated with conditioned media from Tg-treated astrocytes, which reduced synaptic density. Liquid chromatography/mass spectrometry of the Tg-conditioned media revealed a reduction in extracellular matrix and cell adhesion pathways important for synaptic integrity. The authors next used a mouse model of prion diseases to investigate the role of astrocytic UPR in vivo. Following disease onset, PERK-P staining was evident in astrocytes, and gene expression analysis revealed a marked increase in the proinflammatory genes identified in UPR-activated primary astrocyte. Overexpressing an active fragment of growth arrest and damaged-inducible protein (GADD34), the specific phosphatase of eIF2α-P selectively in astrocytes lowered the astrocytic activation in the hippocampus in prion-infected mice. These anti-inflammatory effects largely prevented hippocampal neurodegeneration, thereby extending survival. These studies identified a distinct reactive state of astrocytes dependent on PERK-P signaling detrimental to neuronal health.

The current study effectively demonstrated PERK signaling in reactive astrocytes from prion-infected mice drives degeneration; however, it remains unclear if the accumulation of misfolded prion protein in astrocytes induced the PERK signaling. Future studies should aim to investigate if the accumulation of misfolded prion in astrocytes or perhaps other proteinopathies in astrocytes induces the reactive state.

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