MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration

Barker, Scarlett J.; Raju, Ravikiran M.; Milman, Noah; Wang, Jun; Dávila-Velderrain, José; Gunter-Rahman, Fatima; Parro, Cameron; Bozzelli, P. Lorenzo; Abdurrob, Fatema; Abdelaal, Karim; Bennett, David A.; Kellis, M; Tsai, Li‐Huei

doi:10.1126/scitranslmed.abd7695

Cited by 59 publications

(47 citation statements)

References 66 publications

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“…Among the synergistic and non-synergistic DEG genes, we identified few AD-known loci (i.e., genes prioritized by previous large GWAS and sequencing studies for AD). For instance, MEF2C , a protective factor against neurodegeneration [ 57 ], is among the synergistically upregulated DEGs in neurons in both organisms (human: logFC = 0.335; p = 0.0067; zebrafish: logFC: 0.297, p = 0.0421). On the other hand, RBFOX1 —an RNA-binding protein found as top signal that is a recent GWAS for amyloid load in AD and involved in amyloid clearance [ 58 ]—is a non-synergistic DEG.…”

Section: Resultsmentioning

confidence: 99%

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Coşacak

Bhattarai

Jager

et al. 2022

Cells

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Neurogenesis is significantly reduced in Alzheimer’s disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10). Approximately 95.4% of the human and zebrafish cells co-clustered. Within each cell type, we identified differentially expressed genes (DEGs), enriched KEGG pathways, and gene ontology terms. We studied synergistic and non-synergistic DEGs to point at either common or uniquely altered mechanisms across species. Using the top DEGs, a high concordance in gene expression changes between species was observed in neuronal clusters. On the other hand, the molecular pathways affected by AD in zebrafish astroglia differed from humans in favor of the neurogenic pathways. The integration of zebrafish and human transcriptomes shows that the zebrafish can be used as a tool to study the cellular response to amyloid proteinopathies. Uniquely altered pathways in zebrafish could highlight the specific mechanisms underlying neurogenesis, which are absent in humans, and could serve as potential candidates for therapeutic developments.

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Section: Resultsmentioning

confidence: 99%

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Coşacak

Bhattarai

Jager

et al. 2022

Cells

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“…Npas4 protects against chemically induced epilepsy [204]. MEF2 is induced in the brain by environmental enrichment and mediates resilience to neurodegeneration [205]. Tumor-suppressive effects are mediated by Egr1 [206,207] and Atf3 [208,209].…”

Section: Adaptive Transcription Exerts Protective and Curative Effectsmentioning

confidence: 99%

The Universal Role of Adaptive Transcription in Health and Disease

Lissek¹

2022

Preprint

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In mammals, adaptive transcription is a crucial mechanism to connect environmental stimulation to changes in gene expression and subsequent organism remodeling. Adaptive transcriptional programs are central to various organism functions, such as learning and memory, immune system plasticity and muscular remodeling, and their activation increases cellular resilience and prevents various diseases. Yet, they also form the basis for many maladaptive processes and are crucially involved in the progression of addiction, depression, cancer, cardiovascular disorders, autoimmune conditions and metabolic dysfunction among others. They are implicated in mediating the therapeutic effects of major treatment modalities such as antidepressants and can have negative effects on treatment efforts such as in radiotherapy resistance in cancer. The present work examines the universal role of adaptive transcription as a mechanism for the induction of cell state transitions in health and disease and explores how some of humanity’s gravest disorders can be seen as adaptive logic errors. It also considers underlying principles in the basic structure of adaptive transcriptional programs such as their division into a core and a directional program and analyses how one might best reprogram cells via complex stimulation patterns to achieve concrete adaptation goals and optimal health of the whole organism.

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“…[11] Barker et al have shown that in the brain the ADTF MEF2A/C is recruited through exposure to enriched environments and its overexpression protects against Alzheimer-like cognitive impairment in mice. [12] SRF is another well-studied ADTF and has been shown to be central to the brain rejuvenation effect of cerebrospinal fluid transfusion from young into old mice. [13] Expression of the IEGs Npas4 and Arc in the hippocampus is reduced in aged memory-impaired mice.…”

Section: Activity-dependent Transcription Factors and Immediate Early...mentioning

confidence: 99%

“…[ 143 ] In the mouse brain, MEF2A/C is recruited through exposure to enriched environments and its overexpression protects against Alzheimer‐like cognitive impairment. [ 12 ] Npas4 is induced in the mouse hippocampus by environmental enrichment and regulates inhibitory synaptic signaling. [ 144 ] Environmental enrichment maintains a young DNA methylation signature in the hippocampus during aging [ 145 ] and stimulates hippocampal neurogenesis in mice.…”

Section: Interventionsmentioning

confidence: 99%

Activity‐Dependent Induction of Younger Biological Phenotypes

Lissek

2022

Advanced Biology

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In several mammalian species, including humans, complex stimulation patterns such as cognitive and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. A framework is introduced here in which activity‐dependent transcriptional programs, induced by these environmental stimuli, move somatic cells such as neurons and muscle cells toward a state that resembles younger cells to allow remodeling and adaptation of the organism. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell–cell communication, and epigenetic information processing, and leads to functional improvements in these areas. The activity‐dependent gene program (ADGP) can be seen as a natural, endogenous cellular reprogramming mechanism that provides deep insight into the principles of inducible improvements in cell and organism function and can guide the development of therapeutic approaches for longevity. Here, these ADGPs are analyzed, exemplary critical molecular nexus points such as cAMP response element‐binding protein, myocyte enhancer factor 2, serum response factor, and c‐Fos are identified, and it is explored how one may leverage them to prevent, attenuate, and reverse human aging‐related decline of body function.

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MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration

Abstract: Mef2 is induced after enrichment in mice, reduces disease-associated hyperexcitability, and is a feature of cognitive resilience in patients with AD.

Cited by 59 publications

References 66 publications

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

The Universal Role of Adaptive Transcription in Health and Disease

Activity‐Dependent Induction of Younger Biological Phenotypes

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