Regulation of lifespan by neural excitation and REST

Zullo, Joseph M.; Drake, Derek; Aron, Liviu; O'Hern, Patrick J.; Dhamne, Sameer C.; Davidsohn, Noah; Mao, Chai An; Klein, William H.; Rotenberg, Alexander; Bennett, David A.; Church, George M.; Colaiácovo, Mónica P.; Yankner, Bruce A.

doi:10.1038/s41586-019-1647-8

Cited by 185 publications

(189 citation statements)

References 62 publications

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“…Alterations of REST expression and/or activity have been associated with the onset of epilepsy, although the precise role of this factor in the progression of the pathology is still debated, and likely depends on the model employed and on the cell type analyzed (Hu et al, 2011;Liu et al, 2012;Patterson et al, 2017). Our findings are consistent with previous studies, which implicated REST in maintaining neuronal homeostasis and reducing the hyperexcitation of the network (Pozzi et al, 2013;Pecoraro-Bisogni et al, 2018;Zullo et al, 2019).…”

Section: Discussionsupporting

confidence: 90%

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Carminati

Buffolo

Rocchi

et al. 2020

Front. Cell. Neurosci.

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RE-1 Silencing Transcription factor (REST) controls several steps in neural development by modulating the expression of a wide range of neural genes. Alterations in REST expression have been associated with the onset of epilepsy; however, whether such alterations are deleterious or represent a protective homeostatic response remains elusive. To study the impact of REST modulation on seizure propensity, we developed a tool for its negative modulation in vivo. The tool is composed of the paired-amphipathic helix 1 (PAH1) domain, a competitive inhibitor of REST activation by mSin3, fused to the light-oxygen-voltage sensing 2 (LOV2) domain of Avena sativa phototropin 1, a molecular switch to alternatively hide or expose the PAH1 inhibitor. We employed the C450A and I539E light-independent AsLOV2 variants to mimic the closed (inactive) and open (active) states of LOV2-PAH1, respectively. Recombinant AAV1/2 viral particles (rAAVs) allowed LOV2-PAH1 expression in HEK293T cells and primary neurons, and efficiently transduced hippocampal neurons in vivo. mRNA expression analysis revealed an increased expression of several neuronal genes in the hippocampi of mice expressing the open probe. AAV-transduced mice received a single dose of kainic acid (KA), a treatment known to induce a transient increase of REST levels in the hippocampus. Remarkably, mice expressing the active variant displayed a reduced number of KA-induced seizures, which were less severe compared to mice carrying the inactive probe. These data support the validity of our tool to modulate REST activity in vivo and the potential impact of REST modulation on epileptogenesis.

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Section: Discussionsupporting

confidence: 90%

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Carminati

Buffolo

Rocchi

et al. 2020

Front. Cell. Neurosci.

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“…To investigate the gene regulatory networks underlying shared and cell-type-specific responses associated with pathological tau, we performed a transcription factor (TF) binding site enrichment analysis and generated TF regulatory networks integrating neuronal-specific ENCODE ChIP-seq data and consensus coexpression networks in AD (Mostafavi et al, 2018). Among the TF networks shared across neuronal subtypes was one centered around REST, a key regulator of neuronal differentiation and neuronal excitability that has been implicated in aging and AD (Lu et al, 2014;Zullo et al, 2019). Cluster Ex3 had a unique set of TF networks that included GABPA, a transcription factor involved in the regulation of mitochondrial genes required for electron transport and oxidative phosphorylation ( Figure 4E and S6) .…”

Section: Transcriptome Signatures Of Tau Pathology Within and Across mentioning

confidence: 99%

Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction

Otero-García

Xue

Shakouri

et al. 2020

Preprint

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Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimer's disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFTbearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating taumediated neurodegeneration and a platform for biomarker and drug target discovery.

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“…Increased Npas4 expression in the prefrontal cortex by theanine may be involved in the suppression of brain atrophy and cognitive decline in aged SAMP10 mice that ingested theanine. Recent data indicates that the suppression of neural excitation by repressor element-1 silencing transcription factor (REST) regulates aging [68]. These studies suppose that increased expression of Npas4 by theanine may play an important role in suppressing aging by reducing stress.…”

Section: Discussionmentioning

confidence: 99%

Theanine, the Main Amino Acid in Tea, Prevents Stress-Induced Brain Atrophy by Modifying Early Stress Responses

et al. 2020

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Chronic stress can impair the health of human brains. An important strategy that may prevent the accumulation of stress may be the consumption of functional foods. When senescence-accelerated mice prone 10 (SAMP10), a stress-sensitive strain, were loaded with stress using imposed male mouse territoriality, brain volume decreased. However, in mice that ingested theanine (6 mg/kg), the main amino acid in tea leaves, brain atrophy was suppressed, even under stress. On the other hand, brain atrophy was not clearly observed in a mouse strain that aged normally (Slc:ddY). The expression level of the transcription factor Npas4 (neuronal PAS domain protein 4), which regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity, decreased in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but increased in mice that ingested theanine. Lipocalin 2 (Lcn2), the expression of which increased in response to stress, was significantly high in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but not in mice that ingested theanine. These data suggest that Npas4 and Lcn2 are involved in the brain atrophy and stress vulnerability of SAMP10 mice, which are prevented by the consumption of theanine, causing changes in the expression of these genes.

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Regulation of lifespan by neural excitation and REST

Cited by 185 publications

References 62 publications

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction

Theanine, the Main Amino Acid in Tea, Prevents Stress-Induced Brain Atrophy by Modifying Early Stress Responses

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