2008
DOI: 10.1523/jneurosci.0185-08.2008
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The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

Abstract: 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 o… Show more

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Cited by 172 publications
(181 citation statements)
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“…The mutant mice are still being characterized, but up to 12 months of age no phenotype is observed. Similarly, the conditional Lrrk2 G2019S model, recently used to identify Lrrk2 and Hsp90 interaction, was reported to have no obvious neuropathological or motor abnormalities at 12 months of age, although primary hippocampal neurons derived from the mice displayed retarded axon outgrowth during neuronal morphogenesis [72]. Given that BAC and conditional models recapitulate expression in a physiological manner, and taking into account the ageassociated and multifactorial etiology of PD, it is perhaps not surprising that single transgenic mouse models do not recapitulate the phenotypic spectrum of disease.…”
Section: Rodent Modelsmentioning
confidence: 97%
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“…The mutant mice are still being characterized, but up to 12 months of age no phenotype is observed. Similarly, the conditional Lrrk2 G2019S model, recently used to identify Lrrk2 and Hsp90 interaction, was reported to have no obvious neuropathological or motor abnormalities at 12 months of age, although primary hippocampal neurons derived from the mice displayed retarded axon outgrowth during neuronal morphogenesis [72]. Given that BAC and conditional models recapitulate expression in a physiological manner, and taking into account the ageassociated and multifactorial etiology of PD, it is perhaps not surprising that single transgenic mouse models do not recapitulate the phenotypic spectrum of disease.…”
Section: Rodent Modelsmentioning
confidence: 97%
“…Supportive evidence in vivo has come from a conditional Lrrk2 G2019S transgenic model in which inhibition of Hsp90 disrupts the association and leads to proteasomal degradation of Lrrk2 [72]. Primary cultures derived from the same mice display axon growth retardation that may be rescued by Hsp90 inhibitors, suggesting that Hsp90 may serve as a target for reducing accumulation of Lrrk2 and its toxic effects.…”
Section: Lrrk2 and The Ubiquitin Proteasomal Degradation Pathwaymentioning
confidence: 99%
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“…As an alternative to kinase inhibitors, Wang et al (2008) demonstrated in a recent issue of The Journal of Neuroscience the feasibility of indirectly downregulating the augmented kinase activity of mutant G2019S LRRK2 by promoting its proteasomal degradation. This was achieved by inhibiting the chaperone activity of the heat shock protein 90 (Hsp90), a binding partner of LRRK2.…”
mentioning
confidence: 99%
“…In their study, Wang et al (2008) used brain extracts from conditional transgenic mice overexpressing G2019S LRRK2, and showed that the mutant LRRK2 formed a stable complex with Hsp90 and cdc37 in vivo , their Fig. 1 B, C (http://www.…”
mentioning
confidence: 99%