Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration

Smith, Heather; Freeman, Oliver; Butcher, Adrian J.; Holmqvist, Staffan; Humoud, Ibrahim; Schätzl, Tobias; Hughes, Daniel T.; Verity, Nicholas; Swinden, Dean; Hayes, Joseph E.; Weerd, Lis de; Rowitch, David H.; Franklin, R. J. M.; Mallucci, Giovanna R.

doi:10.1016/j.neuron.2019.12.014

Cited by 165 publications

(186 citation statements)

References 42 publications

(43 reference statements)

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“…While it remains unclear in which cell types these changes occur, neuronal overexpression of GADD34 globally decreased eIF2a phosphorylation in hippocampal extracts, rescued the reduced translation and neuronal loss, and increased survival. More recently, the same group could show that also astrocytic overexpression of GADD34 was neuroprotective and increased survival (Smith et al, 2020), highlighting the importance of astrocytes in neurodegeneration. Interestingly, in our PrD mouse model none of the analyzed cell types showed a differential translation of Actb, Snap25, Psd95 (Dlg4), or Chop and only microglia showed an increased translation of Atf4.…”

Section: Discussionmentioning

confidence: 93%

Prions induce minor genome-wide translational changes in neurons compared to glia

Scheckel

Imeri

Schwarz

et al. 2020

Preprint

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Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc causes a robust, reproducible and specific disease manifestation. Here we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

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Section: Discussionmentioning

confidence: 93%

Prions induce minor genome-wide translational changes in neurons compared to glia

Scheckel

Imeri

Schwarz

et al. 2020

Preprint

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“…GSK2606414 ameliorates molecular underpinnings of neurodegeneration including neuronal loss, cognitive dysfunction, and pathological protein accumulation in a variety of disease models (11)(12)(13)(14)(15)(16)18). These studies established that the benefits of GSK2606414 were conferred by inhibition of its primary target, PERK, which was upregulated in disease.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we report the use of a multi-target kinase inhibitor, GSK2606414 or 414, to treat tau transgenic mice in a proof-of-concept study to evaluate whether such strategies can mitigate the early negative outcomes of tauopathy. This compound potently inhibits multiple tyrosine and serine/threonine kinases at low micromolar concentrations (10) and ameliorates phenotypes in a variety of neurological disorder and neurodegenerative models (11)(12)(13)(14)(15)(16). The targets of 414 include kinases involved in tauopathy pathogenesis, including protein kinase R-like endoplasmic reticulum kinase, or PERK (10)(11)(12), the MAPK cascade (10), receptor-interacting serine/threonine-protein kinase 1, or RIPK1 (17), and KIT (18).…”

Section: Introductionmentioning

confidence: 99%

Broad kinase inhibition mitigates early neuronal dysfunction and cognitive deficits in tauopathy

Koren

Hamm

Cloyd

et al. 2020

Preprint

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Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human AD proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy.

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“…Astrocytes can also prune synapses to refine neural circuitry to ultimately modulate synaptic plasticity [ 202 ]. However, dysfunctional and reactive astrocytes can gain neurotoxic properties following brain injury in the ageing brain and in certain neurodegenerative disorders [ 203 , 204 ].…”

Section: Cns Prion Diseasementioning

confidence: 99%

“…The accumulation of misfolded PrP Sc in the brain during prion disease triggers the unfolded protein response (UPR) [ 207 ]. This alters the astrocyte secretome, reduces their synaptogenic properties and stimulates the production of neurotoxic factors which together enhance the rate of neurodegeneration [ 203 ]. Specifically, phosphorylation of PERK signalling in astrocytes causes the transient shutdown of protein synthesis via phosphorylation of eIF2α.…”

Section: Cns Prion Diseasementioning

confidence: 99%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

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Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration

Cited by 165 publications

References 42 publications

Prions induce minor genome-wide translational changes in neurons compared to glia

Prions induce minor genome-wide translational changes in neurons compared to glia

Broad kinase inhibition mitigates early neuronal dysfunction and cognitive deficits in tauopathy

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

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