CHIP-ping away at tau

Goryunov, Dmitry; Liem, Ronald K.H.

doi:10.1172/jci31505

Cited by 18 publications

(16 citation statements)

References 18 publications

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“…The Hsp90 inhibitor-induced suppression of LRRK2 expression is mediated by the proteasome-dependent protein degradation pathway Hsp90 client proteins tend to be degraded via the proteasomedependent pathway during chaperone inhibition (Goryunov and Liem, 2007). Concordantly, the GA-induced suppression of mutant and endogenous LRRK2 was selectively blocked by a proteasome inhibitor, MG132, but not the lysosome inhibitor chloroquine in neurons (Fig.…”

Section: Hsp90 Regulates the Stability Of Lrrk2mentioning

confidence: 88%

The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

Wang¹,

et al. 2008

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Parkinson's disease (PD), a progressive neurodegenerative disease characterized by bradykinesia, rigidity, and resting tremor, is the most common neurodegenerative movement disorder. Although the majority of PD cases are sporadic, some are inherited, including those caused by leucine-rich repeat kinase 2 (LRRK2) mutations. The substitution of serine for glycine at position 2019 (G2019S) in the kinase domain of LRRK2 represents the most prevalent genetic mutation in both familial and apparently sporadic cases of PD. Because mutations in LRRK2 are likely associated with a toxic gain of function, destabilization of LRRK2 may be a novel way to limit its detrimental effects. Here we show that LRRK2 forms a complex with heat shock protein 90 (Hsp90) in vivo and that inhibition of Hsp90 disrupts the association of Hsp90 with LRRK2 and leads to proteasomal degradation of LRRK2. Hsp90 inhibitors may therefore limit the mutant LRRK2-elicited toxicity to neurons. As a proof of principle, we show that Hsp90 inhibitors rescue the axon growth retardation caused by overexpression of the LRRK2 G2019S mutation in neurons. Therefore, inhibition of LRRK2 kinase activity can be achieved by blocking Hsp90-mediated chaperone activity and Hsp90 inhibitors may serve as potential anti-PD drugs.

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Section: Hsp90 Regulates the Stability Of Lrrk2mentioning

confidence: 88%

The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

Wang¹,

et al. 2008

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“…Several Cu(II) ion chelators have been considered as drug candidates, for example, Clioquinol and Apocyclen. Therapeutic approaches for reduction of phosphorylated tau include pharmacologic manipulation of cellular protein refolding/ degradation pathways 8 and immunotherapy. 9 It is evident from the above discussion that there are many pathways that contribute to AD.…”

mentioning

confidence: 99%

“Clicked” Sugar–Curcumin Conjugate: Modulator of Amyloid-β and Tau Peptide Aggregation at Ultralow Concentrations

Dolai¹,

Shi

Corbo³

et al. 2011

ACS Chem. Neurosci.

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The synthesis of a water/plasma soluble, noncytotoxic, "clicked" sugar-derivative of curcumin with amplified bioefficacy in modulating amyloid-β and tau peptide aggregation is presented. Curcumin inhibits amyloid-β and tau peptide aggregation at micromolar concentrations; the sugar−curcumin conjugate inhibits Aβ and tau peptide aggregation at concentrations as low as 8 nM and 0.1 nM, respectively. In comparison to curcumin, this conveniently synthesized Alzheimer's drug candidate is a more powerful antioxidant.

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“…These results suggest that the activity of Hsp70 and Hsp90 preserve the native structure and function of tau protein. Hsp70 and the C-terminal Hsp70-interacting protein (Chip) have been shown to regulate tau ubiquitination and degradation (11,12,21,52,65). Interestingly, Chip and ␤APP interact, and Chip and Hsp70/90 expression have been shown to lower the cellular levels of A␤ and reduce A␤ toxicity in vitro (39).…”

mentioning

confidence: 99%

Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β

Eroglu

Moskophidis

Mivechi

2010

Molecular and Cellular Biology

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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 (APP␤sw) leads to selective appearance of insoluble amyloid ␤42 (A␤42), suggesting an essential role for Hsp110 in APP processing and A␤ 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.

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CHIP-ping away at tau

Cited by 18 publications

References 18 publications

The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

“Clicked” Sugar–Curcumin Conjugate: Modulator of Amyloid-β and Tau Peptide Aggregation at Ultralow Concentrations

Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β

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