The accumulation of misfolded proteins in neurons is a cell stressor that triggers the unfolded protein response (UPR), which restores protein homeostasis and is dysregulated in neurodegenerative disease. One branch of the UPR involving protein-kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) halts protein synthesis and can lead to neuronal loss. Little is known about UPR dysregulation in astrocytes, which provide crucial trophic support to neurons. Astrocytes in an activated, ‘reactive’ state are often observed in neurodegenerative disorders, and here, Smith et al. show that dysregulated PERK–eIF2α signalling in reactive astrocytes alters their secretome and induces synaptic loss and behavioural deficits in a mouse model of prion disease.

First, the authors investigated the effects of UPR activation in primary cultures of mouse hippocampal astrocytes. Exposure to the ER stressor thapsigargin (Thaps) resulted in PERK–eIF2α activation within 2 h, and increased expression of several markers of a reactive, neurotoxic state. These markers were substantially reduced by PERK inhibition, suggesting that PERK signalling is a key driver of this distinct ‘UPR-reactivity’ profile.

Next, the authors tested astrocyte-conditioned medium (ACM) from UPR-reactive astrocytes on primary hippocampal neuron cultures. Whereas ACM from control astrocytes increased synaptic density, ACM from UPR-reactive astrocytes had no effect, but the synaptogenic effect was restored in the presence of a PERK inhibitor. Further analysis revealed that control ACM contained various synaptogenic factors such as collagen, fibronectin and glypican 4 that were reduced in ACM from Thaps-treated astrocytes. Notably, Thaps‒ACM contained increases in chaperone proteins, indicating that the secretome alterations reflect a specific state rather than a general downregulation of protein synthesis.

Last, the authors investigated UPR-reactive astrocytes in the tg37+/– mouse model of prion disease. In this model, increasing levels of prion protein induce PERK–eIF2α signalling, which leads to neuronal loss in the hippocampus, followed by more widespread neurodegeneration and behavioural symptoms. As in the Thaps-treated astrocytes, astrocytes of tg37+/– mice exhibited concurrent elevations in PERK–eIF2α signalling and expression of UPR-reactive state markers. Disruption of PERK–eIF2α signalling selectively in astrocytes of tg37+/– mice reduced the expression of UPR-reactive state markers. Moreover, inhibition of PERK–eIF2α signalling in tg37+/– mice reduced spongiform degeneration substantially, prevented hippocampal neurodegeneration, reduced astrocyte density and reactive astrocyte morphology, and increased survival. Together, these findings suggest that PERK–eIF2α signalling in reactive astrocytes contributes to neurodegeneration by disrupting trophic support.