PubMed: 25374103

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes.
Journal of Alzheimer's disease : JAD
Polydoro M | Saidi LJ | Kay KR | Sanchez L | Hyman BT | Mandelkow EM | Spires-Jones TL

Evidence 938e962280

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles.

Evidence 4802bc07d9

Several publications suggest that molecular chaperones, e.g., heat shock protein 70 and 90 (Hsp70, Hsp90) play a fundamental role in the clearance of misfolded proteins including tau [12].

Evidence a0c99d20e6

The overexpression of full-length tau in Chinese hamster ovary (CHO) cells [3], N2A cells [4], cultured retinal ganglion cells [4], NB2a/d1 cells [5] H4-cells [6], and primary cortical neuron cultures [6] led to an impairment of anterograde transport of a variety of kinesin cargos, including mitochondria

Evidence 56e1e98ca4

This leads to accumulation of mitochondria in the cell body where they cluster near the microtubule center [6].

Evidence 3a32acbde7

Thies and Mandelkow [7] have shown previously that the co-expression of microtubule-associated protein/microtubule affinityregulating kinase 2 (MARK2) with tau can rescue these effects caused by tau overexpression in vitro.

Evidence c242423bba

Misfolded tau proteins, like other natively unfolded molecules, can be detected and cleared by chaperone assisted mechanisms [13].

Evidence 01ee96c454

As expected, we observed a significant impairment of mitochondrial distribution with overexpression of all three tau constructs (p < 0.0001, Wilcoxon test for GFP control versus 4R-tau, GFP versus tauC3, and GFP versus K18ΔK280) (Fig. 5).

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Taken together, these data indicate that tau-overexpression leads to abnormal mitochondrial trafficking that can be rescued by CHIP-co-expression

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CHIP co-expression led to a significant recovery in the area of mitochondria around the nucleus (19–26%).

Evidence 68d6ab60e2

The two major pathways for protein degradation in cells are through the ubiquitin-proteasome system and the autophagy-lysosome system [10, 11], both of which have been implicated in tau degradation in AD [12].

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The tau-protein is a natively soluble protein that plays a key role in the dynamics of microtubules

Evidence 5347afe0da

Recent data suggest that a critical mediator of refolding or clearance of hyperphosphorylated tau is via the HSP70/HSP90 heat shock pathways in which a specific E3 ubiquitin ligase, CHIP (carboxy terminus Hsp70 interacting protein), can recognize and target for degradation abnormal but not normal tau molecules [14–16].

Evidence 5fff8a7741

CHIP is also implicated in regulation of Caspase 3 activity

Evidence 9cc1f97745

CHIP interacts more strongly with tauΔC than full-length tau [18], suggesting it is involved in caspase cleaved tau degradation

Evidence 6556a5b0c7

Dolan et al. [20] showed that CHIP interacts more strongly with tauC3 than full length tau.

Evidence 88ee93c34a

Recent data suggest that caspases are involved in the accumulation of tau pathology [10, 25, 26], and reductions in CHIP have been shown to cause caspase activation and increased caspase-cleaved tau levels [19].

Evidence 3ddca5dbaa

These results indicate that CHIP is involved in degradation of caspases and caspase-cleaved tau.

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Toxicity assays revealed that neither CHIP nor any of the tau constructs caused cell death compared to the control GFP vector (Supplementary Fig. 1).

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The co-chaperone CHIP interacts with Hsp70/Hsp90 to bind unfolded and misfolded proteins

Evidence 684c383cc2

Either of these domains could be critical for degradation of tau since ubiquitination targets proteins for degradation and CHIP is known to interact with full-length tau in a complex with Hsc70/Hsp70 and poly-ubiquitinated tau [17].

Evidence 824367d838

After cyclohexamide treatment, we could still detect a significant decrease in tau levels in cells that were co-transfected with CHIP indicating that the reduction in tau levels due to CHIP is due to degradation and not to transcriptional down-regulation (Supplementary Fig. 3).

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Tau overexpression increased active caspase 3 levels, and co-expression of CHIP reduced cleaved caspase 3 levels compared to tau expression alone (Fig. 3).

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Interestingly, a significant decrease in tau levels was seen with the co-transfection of CHIPΔU (U-box deleted) when transfected with either K18ΔK280 or 4R-Tau.

Evidence 693fe9f6f9

Densitometry analysis of total tau levels of H4- cell lysates on SDS-PAGE showed a 2.0 to 2.5 fold lower levels of tau (4R-tau, tauC3, and K18ΔK280) with co-expression with CHIP, respectively (Fig. 1).

Evidence 4f32369f11

Probing for phospho-tau with the 12E8 antibody in cell lysates from K18ΔK280 transfected cells reveals that tau phosphorylation is also decreased by CHIP overexpression (Fig. 1).

Evidence 49124d2f62

Co-transfection of CHIP with 4R-tau leads to a significant increase in Hsp70 levels, however this is not the case with wither tauC3 or K18DK280 constructs (Supplementary Fig. 2) suggesting that increased HSP70 protein levels are not necessary for the observed reduction in tau levels.

Evidence ed151dd0b1

Indeed, the co-expression of CHIP caused a significant decrease tauC3 in vitro (Fig. 4).

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In CHIP knockout mice, Caspase 3 activation is increased and caspase-cleaved tau levels are increased [17].

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CHIP has two important domains for his chaperone activity: the amino terminus tetratricopeptide repeat (TPR) domain that links CHIP to Hsp70 and Hsp90 [24] and the carboxyl terminus containing the U-box that is important for the E3 ubiquitin ligase function of CHIP.


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