Affiliation:
1. Center for Molecular Chaperone/Radiobiology and Cancer Virology
2. Medical College of Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia 30912
3. Charlie Norwood VA Medical Center, Augusta, Georgia 30904
Abstract
ABSTRACT
Accumulation of tau into neurofibrillary tangles is a pathological consequence of Alzheimer's disease and other tauopathies. Failures of the quality control mechanisms by the heat shock proteins (Hsps) positively correlate with the appearance of such neurodegenerative diseases. However,
in vivo
genetic evidence for the roles of Hsps in neurodegeneration remains elusive. Hsp110 is a nucleotide exchange factor for Hsp70, and direct substrate binding to Hsp110 may facilitate substrate folding. Hsp70 complexes have been implicated in tau phosphorylation state and amyloid precursor protein (APP) processing. To provide evidence for a role for Hsp110 in central nervous system homeostasis, we have generated
hsp110
−
/
−
mice. Our results show that
hsp110
−
/
−
mice exhibit accumulation of hyperphosphorylated-tau (p-tau) and neurodegeneration. We also demonstrate that Hsp110 is in complexes with tau, other molecular chaperones, and protein phosphatase 2A (PP2A). Surprisingly, high levels of PP2A remain bound to tau but with significantly reduced activity in brain extracts from aged
hsp110
−
/
−
mice compared to brain extracts from wild-type mice. Mice deficient in the Hsp110 partner (Hsp70) also exhibit a phenotype comparable to that of
hsp110
−
/
−
mice, confirming a critical role for Hsp110-Hsp70 in maintaining tau in its unphosphorylated form during aging. In addition, crossing
hsp110
−
/
−
mice with mice overexpressing mutant APP (APPβsw) leads to selective appearance of insoluble amyloid β42 (Aβ42), suggesting an essential role for Hsp110 in APP processing and Aβ generation. Thus, our findings provide
in vivo
evidence that Hsp110 plays a critical function in tau phosphorylation state through maintenance of efficient PP2A activity, confirming its role in pathogenesis of Alzheimer's disease and other tauopathies.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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