Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model

Autophagy, Journal Year: 2024, Volume and Issue: 20(12), P. 2655 - 2676

Published: July 25, 2024

Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 promoting degradation of PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy form for removal damaged superfluous mitochondria autophagy-lysosome pathway. Here, we report surprising discovery that, spautin-1 as an effective inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, facilitates stabilization activation full-length PINK1 at outer membrane (OMM) binding to components TOMM complex (TOMM70 TOMM20), leading disruption import prevention PARL-mediated cleavage. Moreover, induces neuronal in

Language: Английский

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The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration

Autophagy Reports, Journal Year: 2025, Volume and Issue: 4(1)

Published: March 10, 2025

Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over lifetime. Autophagy, a key homeostatic quality control system, plays central role not only in neuronal development survival/cell death, but also regulating activity plasticity. Glutamate is major excitatory neurotransmitter that activates downstream targets, with learning memory. However, an excess glutamatergic stimulation pathological stroke, epilepsy neurodegeneration, triggering excitotoxic cell death or sublethal process mitochondrial calcium toxicity (EMT) triggers dendritic retraction. Markers autophagy mitophagy are often elevated following injuries, potential to influence neurodegenerative outcomes these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) PTEN-induced 1 (PINK1), two kinases linked autophagy, Parkinson disease, play important roles handling, density function, maturation spines. Mutations LRRK2, PINK1, proteins Alzheimer's disease perturb handling sensitize neurons injury. While can both protective harmful roles, studies various excitotoxicity stroke models implicate pathogenic role. Understanding autophagic degradation loss injuries has therapeutic implications for acute chronic neurological disorders.

Language: Английский

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iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification

American Journal Of Pathology, Journal Year: 2022, Volume and Issue: 193(2), P. 201 - 212

Published: Nov. 19, 2022

Language: Английский

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Postnatal Allergic Inhalation Induces Glial Inflammation in the Olfactory Bulb and Leads to Autism-Like Traits in Mice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10464 - 10464

Published: Sept. 28, 2024

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders. To explore its pathophysiology, we investigated association between neonatal allergic exposure and behavioral changes. Adult female C57BL/6J mice were immunized with adjuvant (aluminum hydroxide) or ovalbumin emulsified adjuvant. After immunization, mated, offspring born at full term. The postnatal dams infants then simultaneously exposed to an allergen (ovalbumin) vehicle via inhalation. weaning, testing histopathological analyses conducted on male offspring. Compared vehicle-exposed offspring, ovalbumin-exposed had decreased sociability increased repetitive behavior, thus representing ASD-like phenotype in mice. Moreover, revealed that astroglial, microglial, eosinophilic infiltration olfactory bulb, as well eosinophils nasal mucosa. also dendritic spine density a lower proportion mature spines, suggesting impairment stimulus-induced synaptogenesis. In conclusion, induced phenotype, rhinitis, which was followed by glial inflammation bulb parenchyma.

Language: Английский

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ERRα regulates synaptic transmission through reactive oxygen species in hippocampal neurons

Heliyon, Journal Year: 2023, Volume and Issue: 10(1), P. e23739 - e23739

Published: Dec. 15, 2023

Reactive oxygen species (ROS) play multiple roles in synaptic transmission, and estrogen-related receptor α (ERRα) is involved regulating ROS production. The purpose of our study was to explore the underlying effect ERRα on production, neurite formation transmission. Our results revealed that knocking down expression affected neuronal neurites dendritic spines, which are basic structures transmission important learning, memory plasticity; moreover, amplitude frequency miniature excitatory postsynaptic currents (mEPSCs) inhibitory (mIPSCs) were decreased. These abnormalities reversed by overexpression human ERRα. Additionally, we also found increased intracellular levels neurons. inhibitor PBN rescued changes induced knockdown. indicate a new possible cellular mechanism affects levels, turn regulate spine

Language: Английский

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