Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases DOI Creative Commons

Adhithiya Charli,

Ying‐Ju Chang, Jie Luo

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: April 17, 2025

Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, highly vulnerable mitochondrial stress; however, cellular molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is expressed in DAergic neurons mediates apoptotic cell death during neurotoxic via caspase-3-mediated proteolytic activation. Herein, further uncovered a key downstream event PKCδ signaling following governs neuronal by dissembling nuclear architecture. Exposing N27 cells complex-1 inhibitor tebufenpyrad (Tebu) induced phosphorylation at T505 activation loop accompanied caspase-3-dependent High-resolution 3D confocal microscopy revealed proteolytically activated cleaved translocates nucleus, colocalizing with Lamin B1. Electron also visualized membrane damage Tebu-treated cells. In silico analyses identified threonine site on B1 (T575) as PKCδ. Interestingly, stably expressing cleavage-resistant mutant failed induce damage, activation, phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown greatly attenuated Tebu-induced Also, studies using B1T575G PKCδ-ΔNLS-overexpressing showed translocation essential for phosphorylating T575 Tebu insult. Additionally, organotypic midbrain slices cultured from PKCδ-/- mouse pups. Postmortem PD brains significantly higher phosphorylation, loss nigral compared age-matched healthy controls, demonstrating translational relevance these findings. Collectively, our data reveal functions disassemble stress-induced death. This mechanistic insight may have important implications etiology age-related diseases resulting well development novel treatment strategies.

Language: Английский

Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases DOI Creative Commons

Adhithiya Charli,

Ying‐Ju Chang, Jie Luo

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: April 17, 2025

Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, highly vulnerable mitochondrial stress; however, cellular molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is expressed in DAergic neurons mediates apoptotic cell death during neurotoxic via caspase-3-mediated proteolytic activation. Herein, further uncovered a key downstream event PKCδ signaling following governs neuronal by dissembling nuclear architecture. Exposing N27 cells complex-1 inhibitor tebufenpyrad (Tebu) induced phosphorylation at T505 activation loop accompanied caspase-3-dependent High-resolution 3D confocal microscopy revealed proteolytically activated cleaved translocates nucleus, colocalizing with Lamin B1. Electron also visualized membrane damage Tebu-treated cells. In silico analyses identified threonine site on B1 (T575) as PKCδ. Interestingly, stably expressing cleavage-resistant mutant failed induce damage, activation, phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown greatly attenuated Tebu-induced Also, studies using B1T575G PKCδ-ΔNLS-overexpressing showed translocation essential for phosphorylating T575 Tebu insult. Additionally, organotypic midbrain slices cultured from PKCδ-/- mouse pups. Postmortem PD brains significantly higher phosphorylation, loss nigral compared age-matched healthy controls, demonstrating translational relevance these findings. Collectively, our data reveal functions disassemble stress-induced death. This mechanistic insight may have important implications etiology age-related diseases resulting well development novel treatment strategies.

Language: Английский

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