In vivo evidence of CHIP up-regulation attenuating tau aggregation.
The carboxyl terminus of heat-shock cognate (Hsc)70-interacting protein (CHIP) is a ubiquitin E3 ligase that can collaborate with molecular chaperones to facilitate protein folding and prevent protein aggregation. Previous studies showed that, together with heat-shock protein (Hsp)70, CHIP can regulate tau ubiquitination and degradation in a cell culture system. Ubiquitinated tau is one component in neurofibrillary tangles (NFTs), which are a major histopathological feature of Alzheimer's disease (AD). However, the precise sequence of events leading to NFT formation and the mechanisms involved remain unclear. To confirm CHIP's role in suppressing NFT formation in vivo, we performed a quantitative analysis of CHIP in human and mouse brains. We found increased levels of CHIP and Hsp70 in AD compared with normal controls. CHIP levels in both AD and controls corresponded directly to Hsp90 levels, but not to Hsp70 or Hsc70 levels. In AD samples, CHIP was inversely proportional to sarkosyl-insoluble tau accumulation. In a JNPL3 mouse brain tauopathy model, CHIP was widely distributed but weakly expressed in spinal cord, which was the most prominent region for tau inclusions and neuronal loss. Protein levels of CHIP in cerebellar regions of JNPL3 mice were significantly higher than in non-transgenic littermates. Human tau was more highly expressed in this region of mouse brains, but only moderate levels of sarkosyl-insoluble tau were detected. This was confirmed when increased insoluble tau accumulation was found in mice lacking CHIP. These findings suggest that increases in CHIP may protect against NFT formation in the early stages of AD. If confirmed, this would indicate that the quality-control machinery in a neuron might play an important role in retarding the pathogenesis of tauopathies.
Sahara
Naruhiko
N
Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, Saitama, Japan.
Murayama
Miyuki
M
Mizoroki
Tatsuya
T
Urushitani
Makoto
M
Imai
Yuzuru
Y
Takahashi
Ryosuke
R
Murata
Shigeo
S
Tanaka
Keiji
K
Takashima
Akihiko
A
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D003643:Death; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D012995:Solubility; D013997:Time Factors; D014018:Tissue Distribution; D014020:Tissue Extracts / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D014020:Tissue Extracts; D016875:tau Proteins; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases