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Chaperone-mediated autophagy sex-specifically regulates neuronal activity by remodeling the synaptic proteome

ABSTRACT: Chaperone-mediated autophagy (CMA) declines in aging and neurodegenerative diseases. CMA loss in neurons leads to neurodegeneration and behavioral changes in mice, but the role of CMA in neuronal physiology is largely unknown. Here, we show that CMA deficiency causes neuronal hyperactivity, disrupted calcium homeostasis and abnormally increased presynaptic neurotransmitter release in females and elevated postsynaptic AMPA signaling in males. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodeling of the presynaptic proteome in females and the postsynaptic proteome in males. We propose that impaired lysosomal degradation of these synaptic proteins may contribute to hyperexcitability in aging and neurodegeneration. Accordingly, we demonstrate that pharmacological CMA activation in an Alzheimer’s disease mouse model normalizes synaptic protein levels and neurotransmission. These findings unveil a role for CMA in the regulation of neuronal excitability and highlight this pathway as a potential target for mitigating age-related decline in neuronal function.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD057545 | Pride | 2025-09-04

REPOSITORIES: Pride

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			Action	DRS
	20221014_Sarah_Rabia_EKO13_NL_4.raw	Raw
	20221014_Sarah_Rabia_EKO13_minus_3.msf	Msf
	20221014_Sarah_Rabia_EKO13_minus_3.raw	Raw
	20221014_Sarah_Rabia_EKO14_NL_8.raw	Raw
	20221014_Sarah_Rabia_EKO14_minus_7.raw	Raw

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Project description:This is a model of one presynaptic and one postsynaptic cell, as described in the article: Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. Wang XJ, Buzsáki G. J Neurosci. 1996 Oct 15;16(20):6402-13. PMID:8815919; Abstract: Fast neuronal oscillations (gamma, 20-80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for the population synchronization, on properties of single cells and the circuit, were identified. These include the following: (1) that the amplitude of spike afterhyperpolarization be above the GABAA synaptic reversal potential; (2) that the ratio between the synaptic decay time constant and the oscillation period be sufficiently large; (3) that the effects of heterogeneities be modest because of a steep frequency-current relationship of fast-spiking neurons. Furthermore, using a population coherence measure, based on coincident firings of neural pairs, it is demonstrated that large-scale network synchronization requires a critical (minimal) average number of synaptic contacts per cell, which is not sensitive to the network size. By changing the GABAA synaptic maximal conductance, synaptic decay time constant, or the mean external excitatory drive to the network, the neuronal firing frequencies were gradually and monotonically varied. By contrast, the network synchronization was found to be high only within a frequency band coinciding with the gamma (20-80 Hz) range. We conclude that the GABAA synaptic transmission provides a suitable mechanism for synchronized gamma oscillations in a sparsely connected network of fast-spiking interneurons. In turn, the interneuronal network can presumably maintain subthreshold oscillations in principal cell populations and serve to synchronize discharges of spatially distributed neurons. The presynaptic and postsynaptic cell have identical parameters and the variables in each cell are identified by using _pre or _post as a postfix to their names. The presynaptic cell influences the postsynaptic one via the synapse (variables and parameters: I_syn, E_syn, g_syn, F, theta_syn, alpha, beta). The applied current to the presynaptic cell, I_app_pre, is set to 2 microA/cm2 for 10 ms as in figure 1C of the article. The dependence of the postsynaptic cell on directly applied current can be investigated in isolation by setting I_app_pre to 0 and altering I_app_post. Originally created by libAntimony v1.4 (using libSBML 3.4.1)

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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Chaperone-mediated autophagy sex-specifically regulates neuronal activity by remodeling the synaptic proteome

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