Dataset Information

E-MTAB-8668

ABSTRACT: Redox activation of excitatory pathways in auditory neurons as mechanism of age-related hearing loss

PROVIDER: E-MTAB-8668 | ExpressionAtlas | 2021-03-22

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-MTAB-8668-analysis-methods.tsv	Tabular
	E-MTAB-8668-analytics.tsv	Tabular
	E-MTAB-8668-apply_fixes_zooma_mappings.done	Other
	E-MTAB-8668-atlasExperimentSummary.Rdata	Rdata
	E-MTAB-8668-configuration.xml	Xml

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Project description:Neurons are postmitotic cells that are highly sensitive to proteotoxic insults and reliant on tight protein quality control. Several forms of autophagy co-exist in neurons to maintain proteostasis. Defective autophagic pathways are one of the key hallmarks of the aging and neurodegenerative brains. Chaperone-mediated autophagy (CMA) declines in neurons in aging and neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease. CMA loss in neurons leads to protein aggregation, neuronal hyperactivity, neurodegeneration, and cognitive decline, all reminiscent of brain again. Conversely, pharmacological enhancement of CMA reduces pathological tau and β-amyloid accumulation, mitigates neuronal hyperactivity and seizure susceptibility and ameliorates cognitive decline in multiple tauopathy mouse models. The molecular mechanism underlying the beneficial role of CMA activation in AD is largely unknow. Furthermore, neuronal hyperactivity has recently been proposed as an early hallmark of AD. However, the mechanisms underlying early neuronal hyperactivity in AD are also not fully understood. To investigate these molecular mechanisms, we performed quantitative proteomics in an AD mouse model in early disease following CMA activation. The study analyzed total as well as aggregating proteome in hippocampus of triple-transgenic (x3TG) AD mice (expressing APPSwe, PS2N141I, and hTauP301L) following CMA activation with CA77.1 from 4-6 months of age. 5-6 samples per group were analyzed. Following bottom-up analysis, the enrichment analysis – GO, Ingenuity pathway analysis (IPA) and String analysis identified several pathways predicting aberrant synaptogenesis and increased activation of excitatory synaptic proteome including glutamate receptor signaling which was corrected by CMA activation. CMA activation also reverted the enrichment of synaptic proteins in the aggregates in early AD hippocampus which may restore their aggregation-driven loss of function.

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E-MTAB-8668

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