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Carbon nanoparticles induce endoplasmic reticulum stress around blood vessels with accumulation of misfolded proteins in the developing brain of offspring.

ABSTRACT: Nano-particulate air pollution threatens developing brains and is epidemiologically related to neurodegenerative diseases involving deposition of misfolded proteins. However, the mechanism underlying developmental neurotoxicity by nanoparticles remains unknown. Here, we report that maternal exposure to low doses of carbon black nanoparticle (CB-NP) induces endoplasmic reticulum (ER) stress associated with accumulation of misfolded proteins. Notably, offspring specifically showed high induction of ER stress in perivascular macrophages and reactive astrocytes only around brain blood vessels, along with accumulation of ?-sheet-rich proteins regarded as misfolded proteins. Our results suggest that maternal CB-NP exposure induced ER stress in PVMs and reactive astrocytes around blood vessels in the brain of offspring in mice. The induction of ER stress accompanied by the perivascular accumulation of misfolded proteins is likely to be associated with perivascular abnormalities and neurodegeneration, and development of neurodegenerative diseases related to particulate air pollution.

SUBMITTER: Onoda A

PROVIDER: S-EPMC7308306 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Carbon nanoparticles induce endoplasmic reticulum stress around blood vessels with accumulation of misfolded proteins in the developing brain of offspring.

Onoda Atsuto A Kawasaki Takayasu T Tsukiyama Koichi K Takeda Ken K Umezawa Masakazu M

Scientific reports 20200622 1

Nano-particulate air pollution threatens developing brains and is epidemiologically related to neurodegenerative diseases involving deposition of misfolded proteins. However, the mechanism underlying developmental neurotoxicity by nanoparticles remains unknown. Here, we report that maternal exposure to low doses of carbon black nanoparticle (CB-NP) induces endoplasmic reticulum (ER) stress associated with accumulation of misfolded proteins. Notably, offspring specifically showed high induction o ...[more]

PMID: 32572058

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Project description:Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes. Since the role of FKBP8 in the heart has not been fully elucidated, the aim of this study is to determine the functional role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient (Fkbp8-/-) mice were generated. Fkbp8-/- mice showed no cardiac phenotypes under baseline conditions. The Fkbp8-/- and control wild type littermates (Fkbp8+/+) mice were subjected to pressure overload by means of transverse aortic constriction (TAC). Fkbp8-/- mice showed left ventricular dysfunction and chamber dilatation with lung congestion 1week after TAC. The number of apoptotic cardiomyocytes was dramatically elevated in TAC-operated Fkbp8-/- hearts, accompanied with an increase in protein levels of cleaved caspase-12 and endoplasmic reticulum (ER) stress markers. Caspase-12 inhibition resulted in the attenuation of hydrogen peroxide-induced apoptotic cell death in FKBP8 knockdown H9c2 myocytes. Immunocytological and immunoprecipitation analyses indicate that FKBP8 is localized to the ER and mitochondria in the isolated cardiomyocytes, interacting with heat shock protein 90. Furthermore, there was accumulation of misfolded protein aggregates in FKBP8 knockdown H9c2 myocytes and electron dense deposits in perinuclear region in TAC-operated Fkbp8-/- hearts. The data suggest that FKBP8 plays a protective role against hemodynamic stress in the heart mediated via inhibition of the accumulation of misfolded proteins and ER-associated apoptosis.

Dataset Information

Carbon nanoparticles induce endoplasmic reticulum stress around blood vessels with accumulation of misfolded proteins in the developing brain of offspring.

Publications

Carbon nanoparticles induce endoplasmic reticulum stress around blood vessels with accumulation of misfolded proteins in the developing brain of offspring.

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