Local Inhibition of PERK Enhances Memory and Reverses Age-Related Deterioration of Cognitive and Neuronal Properties

Sharma, Vidya; Ounallah-Saad, Hadile; Chakraborty, Darpan; Hleihil, Mohammad; Sood, Rapita; Barrera, Iliana; Edry, Efrat; Chandran, Sailendrakumar Kolatt; Leon, Shlomo Ben Tabou de; Kaphzan, Hanoch; Rosenblum, Kobi

doi:10.1523/jneurosci.0628-17.2017

Cited by 87 publications

(87 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PERK is a key regulator of eIF2-dependent translation, which is a key molecular process underlying learning and memory formation 24–26 . To determine whether the conditional deletion of PERK in DA neurons impacts cognitive, as well as motor function, we examined 3- and 12-month old PERK f/f DAT-Cre mice and age-matched littermate WT DAT-Cre mice in a series of behavioral tasks to test learning and memory.…”

Section: Resultsmentioning

confidence: 99%

“…Classically, eIF2α-mediated translational control in the brain has been studied in the context of synaptic plasticity as well as learning and memory processes 5,56 , with most of the studies focusing on molecular manipulation in excitatory neurons 17, 25, 26 . Our findings reveal a previously unrecognized role of PERK-eIF2α-mediated translation in DA neurons and provide molecular insights into the pathophysiology of motor and cognitive impairments when this type of translational control is disrupted.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic reduction of PERK-eIF2α signaling in dopaminergic neurons drives cognitive and age-dependent motor dysfunction

Longo

Mancini

Ibraheem

et al. 2020

Preprint

View full text Add to dashboard Cite

2An array of phenotypes in animal models of neurodegenerative disease have been shown to 3 be reversed by neuronal inhibition of PERK, an eIF2α kinase that modulates the unfolded 4 protein response (UPR). This suggests that targeting PERK therapeutically could be beneficial 5 for treatment of human disease. Herein, using multiple genetic approaches we show that 6 selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in 7 multiple cognitive and age-dependent motor phenotypes. Conditional expression of phospho-8 mutant eIF2 in DA neurons recapitulated the phenotypes caused by deletion of PERK, 9 consistent with a causal role of decreased eIF2 phosphorylation. In addition, deletion of 10 PERK in DA neurons resulted in altered de novo translation, as well as age-dependent 11 changes in axonal DA release and uptake in the striatum that mirror the pattern of motor 12 changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α 13 signaling in DA neurons is required for normal cognitive and motor function across lifespan, 14 and also highlight the need for caution in the proposed use of sustained PERK inhibition in 15 neurons as a therapeutic strategy in the treatment of neurodegenerative disorders.In order to evaluate whether proper cell type-specific regulation of PERK-eIF2 105 signaling in DA neurons is required for normal cognitive and motor function, we generated 106 mice containing a DA transporter (DAT) promoter-driven Cre transgene (DAT-Cre; Jackson 107 Laboratory, stock number: 006660) 21 and a conditional allele of Perk (Perk loxP ; termed PERK f/f ; 108 Fig. 1a) 22 . The expression of the Cre transgene and the Perk loxP allele was determined using 109 PCR-specific primers (Fig. 1b). The resulting conditional knockout mice (PERK f/f DAT-Cre), 110 which lack PERK in DA neurons of both the ventral tegmental area (VTA) and the substantia 111 nigra pars compacta (SNc) represent the primary experimental mouse line used here, along 112 with their littermate control mice (WT DAT-Cre). 114Cell-specific deletion of PERK in DA neurons was first verified at the protein expression 115 level by treating coronal midbrain slices containing the VTA and SNc with thapsigargin, which 116 inhibits ER Ca 2+ sequestration and is a potent inducer of ER stress and eIF2 phosphorylation. 117Immunostaining for PERK after thapsigargin exposure was clearly seen in tyrosine-118 hydroxylase positive (TH+) DA neurons in both SNc and VTA in WT DAT-Cre mice, whereas 119 PERK staining was not detected in SNc or VTA DA neurons of PERK f/f DAT-Cre mice, 120 although PERK expression in non-DA (TH-) cells remained intact ( Fig. 1c-d). Consistent with 121 these results, downstream UPR targets of PERK such as p-eIF2 ( Supplementary Fig. 1a-d) 122 and ATF4 ( Supplementary Fig. 1e-f) were significantly reduced in both SNc and VTA DA 123 neurons of PERK f/f DAT-Cre mice compared to thapsigargin-treated controls. Taken together, 124 these results demonstrate a reduced UPR after thapsigargin...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic reduction of PERK-eIF2α signaling in dopaminergic neurons drives cognitive and age-dependent motor dysfunction

Longo

Mancini

Ibraheem

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Although rarely discussed in the past literature, EXOSC4 is known to be related to the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, encoded by the EIF2AK3 gene), which regulates gene expression [38]. A recent study reported that locally reduced PERK expression or activity could enhance neuronal excitability and improve memory and cognitive function in young mice [39]. Another study provided evidence that PERK is a key regulator of memory impairments and neurodegeneration in Alzheimer's disease [40].…”

Section: Discussionmentioning

confidence: 99%

Causal relationships between genetically determined metabolites and human intelligence: A Mendelian randomization study

Yang

Zhao

et al. 2020

Preprint

View full text Add to dashboard Cite

Intelligence predicts important life and health outcomes, but the biological mechanisms underlying differences in intelligence are not yet understood. The use of genetically determined metabotypes (GDMs) to understand the role of genetic and environmental factors, and their interactions, in human complex traits has been recently proposed. However, this strategy has not been applied to human intelligence. Here we implemented a two-sample Mendelian randomization (MR) analysis using GDMs to assess the causal relationships between genetically determined metabolites and human intelligence. The standard inverse-variance weighted (IVW) method was used for the primary MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Using 25 genetic variants as instrumental variables (IVs), our study found that 5-oxoproline was associated with better performance in human intelligence tests (P IVW = 9 · 25×10 -5 ). The causal relationship was robust when sensitivity analyses were applied (P MR-Egger = 0 · 0001, P Weighted median = 6 · 29×10 -6 , P MR-PRESSO = 0 · 0007), and no evidence of horizontal pleiotropy was observed. Similarly, also dihomo-linoleate (20:2n6) and p-acetamidophenylglucuronide showed robust association with intelligence. Our study provides novel insight by integrating genomics and metabolomics to estimate causal effects of genetically determined metabolites on human intelligence, which help to understanding of the biological mechanisms related to human intelligence.

show abstract

“…Protein translation overload is temporarily halted by PERK; hence, the function of PERK is extremely important for easing the UPR. PERK is functionally essential for deciding neuronal fate because it is a crucial mediator of ER stress [115], and numerous pharmacological agents are capable of targeting the UPR and ER stress components. Thus, existing approaches to treat ICH can be combined with pharmacological agents that can directly activate or deactivate ER stress components, which might play a critical role in alleviating post-ICH symptoms.…”

Section: Er Stress Components and Ich Therapeutic Strategiesmentioning

confidence: 99%

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Thangameeran

Tsai

Hung

et al. 2020

Cells

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) is an intracellular organelle that performs multiple functions, such as lipid biosynthesis, protein folding, and maintaining intracellular calcium homeostasis. Thus, conditions wherein the ER is unable to fold proteins is defined as ER stress, and an inbuilt quality control mechanism, called the unfolded protein response (UPR), is activated during ER stress, which serves as a recovery system that inhibits protein synthesis. Further, based on the severity of ER stress, the response could involve both proapoptotic and antiapoptotic phases. Intracerebral hemorrhage (ICH) is the second most common subtype of cerebral stroke and many lines of evidence have suggested a role for the ER in major neurological disorders. The injury mechanism during ICH includes hematoma formation, which in turn leads to inflammation, elevated intracranial pressure, and edema. a proper understanding of the injury mechanism(s) is required to effectively treat ICH and closing the gap between our current understanding of ER stress mechanisms and ICH injury can lead to valuable advances in the clinical management of ICH.Cells 2020, 9, 750 2 of 20 because of cardiovascular conditions, with hypertension playing a major role. PBI is characterized by mechanical injury followed by a mass effect with the initial ictus causing physical tissue disruption that then leads to pathophysiological conditions in the brain.A sudden rise in intracranial hematoma volume causes an increase in barotrauma and reduces blood flow to the area of the ictus [4,5]. Typically, PBI is followed by SBI, which is considered as a devastating stage after ICH, and the severity of SBI depends on the rate of recovery and location of the ICH. SBI involves the neuroinflammatory response to the triggering of the coagulation cascade through activation of the immune system. The inflammation size is based on the volume and position of the hematoma [5][6][7]. The various pathological factors responsible for SBI include the host immune response, release of thrombin, release of clot components (iron and heme)

show abstract

Local Inhibition of PERK Enhances Memory and Reverses Age-Related Deterioration of Cognitive and Neuronal Properties

Cited by 87 publications

References 71 publications

Genetic reduction of PERK-eIF2α signaling in dopaminergic neurons drives cognitive and age-dependent motor dysfunction

Genetic reduction of PERK-eIF2α signaling in dopaminergic neurons drives cognitive and age-dependent motor dysfunction

Causal relationships between genetically determined metabolites and human intelligence: A Mendelian randomization study

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Contact Info

Product

Resources

About