Heat Shock Protein 90 Modulates LRRK2 Stability: Potential Implications for Parkinson's Disease Treatment

Hurtado-Lorenzo, Andrés; Anand, Vasanti S.

doi:10.1523/jneurosci.1870-08.2008

Cited by 15 publications

(9 citation statements)

References 12 publications

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“…8B). All but one of these hubs have been implicated in PD: AKT1 (37 edges) 70,71 , HGS (26 edges), CDC37/HSP90 (22 edges) 72,73 , STUB1/CHIP (20 edges) 74 , and HSPA1A (22 edges) 75–77 (Fig. 7B).…”

Section: Resultsmentioning

confidence: 99%

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Gonzalez¹,

Garitaonandia²,

Poustovoitov³

et al. 2016

Cell Transplant

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Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cellderived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immuno suppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

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Section: Resultsmentioning

confidence: 99%

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Gonzalez¹,

Garitaonandia²,

Poustovoitov³

et al. 2016

Cell Transplant

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“…This work adds weight to an emerging model, in which key proteins involved in the etiology of Parkinson’s disease are constituents of a functionally specialized network, or possibly multiple networks, of protein–protein interactions with Hsc70/Hsp90 chaperones at its core, with Pink1 and Lrrk2 as clients and with direct connections to the proteasome through the interaction of Hsc70 with two ubiquitin 3 ligases, parkin, and the carboxyl terminus of Hsc70-interacting protein (CHIP) . Possible links of this network to α-synuclein biology have been proposed before , and may involve an interaction of Hsc70 with the cysteine-string protein and small glutamine-rich tetratricopeptide repeat-containing protein (SGT). , In support of a central involvement of the Hsc70/90 chaperone network in Parkinson's disease, (i) Pink1 has been shown to be stabilized by Hsp90; − (ii) LRRK2 has been shown to be stabilized by the carboxyl terminus of CHIP; − (iii) Hsp90 has been shown to regulate recycling of extracellular α-synuclein; (iv) parkin has been shown to associate with Hsc70 and possibly mediate the degradation-independent ubiquitination of Hsc70; (v) Hsc70 expression has been documented to prevent α-synuclein-dependent and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-dependent dopaminergic degeneration in Drosophila and mouse models of Parkinson’s disease; (vi) the distribution of the constitutive Hsc70 rather than the inducible Hsp70 has been observed to be altered in PD; and (vii) post-mortem Lewy bodies have been shown to immunostain for Hsc70 and Hsp90 …”

Section: Discussionmentioning

confidence: 99%

Choice of Biological Source Material Supersedes Oxidative Stress in Its Influence on DJ-1 in Vivo Interactions with Hsp90

et al. 2011

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DJ-1 is a small but relatively abundant protein of unknown function that may undergo stressdependent cellular translocation and has been implicated in both neurodegenerative diseases and cancer. As such, DJ-1 may be an excellent study object to elucidate the relative influence of the cellular context on its interactome and for exploring whether acute exposure to oxidative stressors alters its molecular environment. Using quantitative mass spectrometry, we conducted comparative DJ-1 interactome analyses from in vivo cross-linked brains or livers and from hydrogen peroxidetreated or naïve embryonic stem cells. The analysis identified a subset of glycolytic enzymes, heat shock proteins 70 and 90, and peroxiredoxins as interactors of DJ-1. Consistent with a role of DJ-1 in Hsp90 chaperone biology, we document destabilization of Hsp90 clients in DJ-1 knockout cells. We further demonstrate the existence of a C106 sulfinic acid modification within DJ-1 and thereby establish that this previously inferred modification also exists in vivo. Our data suggest that caution has to be exerted in interpreting interactome data obtained from a single biological source material and identify a role of DJ-1 as an oxidative stress sensor and partner of a molecular machinery notorious for its involvement in cell fate decisions.

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“…The molecular chaperone, Hsp90, and its co‐chaperone, p50 cdc37 , were found to interact with LRRK2 through its kinase domain, and to be necessary for assisting in proper folding and activation of the kinase [8]. Furthermore, Hsp90 has been demonstrated to form a complex with LRRK2 in vivo , and inhibition of Hsp90 was found to block this association, leading to proteasomal degradation of LRRK2 [40–42]. On the basis of this observation, it has been suggested that Hsp90 inhibitors may have therapeutic potential in reducing LRRK2 levels and, subsequently, be beneficial therapeutics for PD.…”

Section: Lrrk2 Interacting Proteinsmentioning

confidence: 99%

LRRK2 in Parkinson’s disease: biochemical functions

Anand

Braithwaite

2009

The FEBS Journal

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Leucine‐rich repeat kinase 2 (LRRK2) is a large, complex, multidomain protein containing kinase and GTPase enzymatic activities and multiple protein–protein interaction domains. Mutations linked to autosomal dominant forms of Parkinson’s disease result in amino acid changes throughout the protein and alterations in both its enzymatic properties and interactions. The best characterized mutation to date, G2019S, leads to increased kinase activity, and mutations in the GTPase domain, such as R1441C and R1441G, have also been reported to influence kinase activity. Therefore, an examination of LRRK2’s properties as a kinase is important for understanding the mechanisms underlying the disorder and has the potential to lead to therapeutics. These findings also suggest that there may be complex interplay between the functional domains of LRRK2. Here, we review LRRK2’s biochemical functions based on structural and kinetic studies of the enzymatic domains, its potential substrates and the role of its interactions. Despite the field’s embryonic understanding of the true relevance of these substrates and interactions, initial studies are providing clues with respect to its pathophysiological functions. Together, these findings should increase our understanding of mechanisms underlying Parkinson’s disease and place LRRK2 as a unique molecular target for effective therapeutic development.

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Heat Shock Protein 90 Modulates LRRK2 Stability: Potential Implications for Parkinson's Disease Treatment

Cited by 15 publications

References 12 publications

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Choice of Biological Source Material Supersedes Oxidative Stress in Its Influence on DJ-1 in Vivo Interactions with Hsp90

LRRK2 in Parkinson’s disease: biochemical functions

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