Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis

Tsaytler, Pavel; Harding, Heather P.; Ron, David; Bertolotti, Anne

doi:10.1126/science.1201396

Cited by 478 publications

(524 citation statements)

References 15 publications

(26 reference statements)

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“…Promoting eIF2a-P dephosphorylation rescues vital translation rates and is thereby neuroprotective, whereas preventing this further reduces translation and enhances neurotoxicity. The data support the development of generic proteostatic approaches 22,28 to therapy-fine-tuning protein synthesis-in prion, and perhaps other neurodegenerative disorders involving protein misfolding. [7][8][9][10] .…”

Section: Research Lettersupporting

confidence: 55%

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Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

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554

617

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The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the a-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2a-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases 1-4 , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2a-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2a-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2a-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2a-P dephosphorylation 5 , increased eIF2a-P levels, exacerbating neurotoxicity and significantly reducing survival in priondiseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.Neurodegenerative diseases pose an ever-increasing challenge for society and health care systems worldwide, but their molecular pathogenesis is still largely unknown and no curative treatments exist. Alzheimer's (AD), Parkinson's (PD) and prion diseases are separate clinical and pathological conditions, but it is likely they share common mechanisms leading to neuronal death. Mice with prion disease show misfolded prion protein (PrP) accumulation and develop extensive neurodegeneration (with profound neurological deficits), in contrast to mouse models of AD or PD, in which neuronal loss is rare. Uniquely therefore, prion-infected mice allow access to mechanisms linking protein misfolding with neuronal death. Prion replication involves the conversion of cellular PrP, PrP C , to its misfolded, aggregating conformer, PrP Sc , a process leading ultimately to neurodegeneration 6 . We have previously shown rescue of neuronal loss and reversal of early cognitive and morphological changes in prion-infected mice by depleting PrP in neurons, preventing prion replication and ab...

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Section: Research Lettersupporting

confidence: 55%

“…Transient eIF2a phosphorylation is beneficial to cells overloaded with misfolded proteins: it reduces protein synthesis and increases availability of chaperones, promoting refolding 22,23 . However, persistently high levels of eIF2a-P are detrimental in vitro 24 .…”

Section: Research Lettermentioning

confidence: 99%

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

Self Cite

554

617

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show abstract

“…Given that inhibition of PP1 results in the inactivation of a large number of holophosphatase complexes with a broad range of substrate specificities, one implication of our findings is that a drug able to block the specific interaction of eIF2α with GADD34-related viral proteins could be a useful approach for the development of antiviral therapies. Notably, salubrinal has been shown to inhibit GADD34-PP1 and CReP-PP1 complexes (40), and guanabenz specifically inhibits formation of the GADD34-PP1 complex (41), suggesting that PP1 regulatory subunits are a druggable target. Finally, although we have identified orthologs of GADD34 containing both the eIF2α-binding site and the PP1-binding motif in different animals and viruses, clear orthologs of GADD34 are absent in plants and fungi.…”

Section: Discussionmentioning

confidence: 99%

An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α

Rojas

Vasconcelos

Dever

2015

Proc. Natl. Acad. Sci. U.S.A.

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Transient protein synthesis inhibition, mediated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α), is an important protective mechanism cells use during stress conditions. Following relief of the stress, the growth arrest and DNA damage-inducible protein GADD34 associates with the broadly acting serine/threonine protein phosphatase 1 (PP1) to dephosphorylate eIF2α. Whereas the PP1-binding motif on GADD34 has been defined, it remains to be determined how GADD34 directs PP1 to specifically dephosphorylate eIF2α. In this report, we map a novel eIF2α-binding motif to the C terminus of GADD34 in a region distinct from where PP1 binds to GADD34. This motif is characterized by the consensus sequence Rx [Gnl], where capital letters are preferred and x is any residue. Point mutations altering the eIF2α-binding motif impair the ability of GADD34 to interact with eIF2α, promote eIF2α dephosphorylation, and suppress PKR toxicity in yeast. Interestingly, this eIF2α-docking motif is conserved among viral orthologs of GADD34, and is necessary for the proteins produced by African swine fever virus, Canarypox virus, and Herpes simplex virus to promote eIF2α dephosphorylation. Taken together, these data indicate that GADD34 and its viral orthologs direct specific dephosphorylation of eIF2α by interacting with both PP1 and eIF2α through independent binding motifs.

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“…Phramacologically prolonging the transient attenuation of translation that occurs upon ER stress may be employed to adjust protein production rates to levels manageable by available chaperones [94]. Increasing proteolytic capacity provides an alternative approach to maintaining proteostasis.…”

Section: The Pn As a Target For Pharmacological Interventionmentioning

confidence: 99%

Proteostasis impairment in protein-misfolding and -aggregation diseases

Hipp

Park

Hartl

2014

Trends in Cell Biology

563

486

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Cells possess an extensive network of components to safeguard proteome integrity and maintain protein homeostasis (proteostasis). When this proteostasis network (PN) declines in performance, as may be the case during aging, newly synthesized proteins are no longer able to fold efficiently and metastable proteins lose their functionally active conformations, particularly under conditions of cell stress. Apart from loss-of-function effects, a critical consequence of PN deficiency is the accumulation of cytotoxic protein aggregates, which are also associated with many age-dependent neurodegenerative diseases and other medical disorders. Here we discuss recent evidence that the chronic production of aberrantly folded and aggregated proteins in these diseases is harmful by overtaxing PN capacity, setting in motion a vicious cycle of increasing proteome imbalance that eventually leads to PN collapse and cell death

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Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis

Cited by 478 publications

References 15 publications

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α

Proteostasis impairment in protein-misfolding and -aggregation diseases

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