RT Journal Article
SR Electronic
T1 Peripherally expressed misfolded proteins remotely disrupt brain function and aggravate stroke-induced brain injury
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 785477
DO 10.1101/785477
A1 Yanying Liu
A1 Kalpana Subedi
A1 Aravind Baride
A1 Svetlana Romanova
A1 Christa C. Huber
A1 Xuejun Wang
A1 Hongmin Wang
YR 2019
UL http://biorxiv.org/content/early/2019/09/30/785477.abstract
AB 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.