Published recently in Neuron, researchers from the UK DRI at Cambridge, led by Prof Giovanna Mallucci, have discovered a harmful reactivity state in astrocytes that compromises these cells’ ability to support neurons. Targeting this new profile may lead to novel therapeutics against the devastating neurodegenerative diseases behind dementia.
Over the past decade, cellular stress - resulting from the accumulation of misfolded proteins - has been implicated as a major driver in the progression of neurodegenerative disease. One consequence of this stress is the activation of the unfolded protein response (UPR) to restore protein homeostasis. However, sustained phosphorylation of the protein PERK in this process leads to a global reduction in protein synthesis through increased eIF2a-P levels, that has been shown to cause synaptic failure and neuronal loss. With the effects of PERK dysregulation already relatively well understood in neurons, the Cambridge group sought to understand whether key support cells – astrocytes – also had a role to play, tackling the research question with multiple approaches.
Using known stressors of the Endoplasmic Reticulum, the researchers confirmed the activation of the PERK signalling pathways in primary mouse astrocytes before observing a shift in astrocyte reactivity distinct from recently described ‘toxic’ and ‘protective’ states, which they coined ‘UPR’-reactive. Exploring the functional consequences of this reactivity state, the group found that secretions from these astrocytes were lacking in the usual synaptogenic factors, e.g. collagen and fibronectin. Inhibiting PERK signalling in these astrocytes restored these factors and promoted synapse growth in primary hippocampal neurons, confirming the pathway’s contribution.
Moving to an in vivo model of prion disease, evidence was found suggesting a similar profile of UPR-reactive astrocytes. To target the PERK signalling pathway in this model, lentiviral vectors were generated to deliver an active fragment of GADD34, a specific phosphatase and inhibitor of the pathway, to astrocytes. The successful inhibition led to a reduction in the UPR-reactivity profile in astrocytes. Furthermore, burrowing behaviour, used to assess early synaptic dysfunction, improved and there was marked neuroprotection and reduction in neuronal degeneration, as well as significant extension of lifespan, comparable to targeting this pathway in neurons.