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Peripherally expressed misfolded proteins remotely disrupt brain function and aggravate stroke-induced brain injury

Yanying Liu, Kalpana Subedi, Aravind Baride, Svetlana Romanova, Christa C. Huber, View ORCID ProfileXuejun Wang, View ORCID ProfileHongmin Wang
doi: https://doi.org/10.1101/785477
Yanying Liu
1Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
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Kalpana Subedi
1Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
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Aravind Baride
2Department of Chemistry, University of South Dakota, Vermillion, SD 57069, USA
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Svetlana Romanova
3Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106
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Christa C. Huber
1Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
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Xuejun Wang
1Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
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  • ORCID record for Xuejun Wang
Hongmin Wang
1Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
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  • ORCID record for Hongmin Wang
  • For correspondence: Hongmin.Wang@usd.edu
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Abstract

Impaired proteostasis has been linked to various diseases, whereas little is known about the impact of peripherally misfolded proteins on the brain. We here studied the brain of mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryABR120G). At baseline, the CryABR120G mice showed impaired cognitive and motor functions, aberrant protein aggregates, neuroinflammation, impaired blood-brain barrier, and reduced proteasome activity in the brain compared with their non-transgenic (Ntg) littermates. Ischemic stroke dramatically exacerbated these pathological alterations and caused more severe brain dysfunction in CryABR120G mice than in the Ntg mice. Intravenously injecting the exosomes isolated from CryABR120G mouse blood into wild-type mice caused the similar phenotypes seen from CryABR120G mice. Importantly, the CryABR120G protein showed the prion-like properties. These results suggest that peripherally misfolded proteins in the heart remotely disrupt brain function through prion-like neuropathology, which may represent an underappreciated mechanism underlying heart-brain crosstalk.

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Posted September 30, 2019.
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Peripherally expressed misfolded proteins remotely disrupt brain function and aggravate stroke-induced brain injury
Yanying Liu, Kalpana Subedi, Aravind Baride, Svetlana Romanova, Christa C. Huber, Xuejun Wang, Hongmin Wang
bioRxiv 785477; doi: https://doi.org/10.1101/785477
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Peripherally expressed misfolded proteins remotely disrupt brain function and aggravate stroke-induced brain injury
Yanying Liu, Kalpana Subedi, Aravind Baride, Svetlana Romanova, Christa C. Huber, Xuejun Wang, Hongmin Wang
bioRxiv 785477; doi: https://doi.org/10.1101/785477

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