Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones

Yang, Chunzhang; Rahimpour, Shervin; Lü, Jie; Pacák, Karel; Ikejiri, Barbara; Brady, Roscoe O.; Zhuang, Zhengping

doi:10.1073/pnas.1221046110

Cited by 68 publications

(74 citation statements)

References 38 publications

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“…Based interrupting its HSP90-mediated degradation while upregulating the molecular chaperone HSP70 and its associated cochaperone BCL2-associated athanogene 3 (BAG3) ( 48 ). These data are supported by additional studies in Gaucher's disease in which reduced ubiquitination and increased stability of mutant GCase was demonstrated after treatment with the HSP70-inducer/HSP90-inhibitors 17-N -allylamino-17-demethoxygeldanamycin, vorinostat, and LB-205 ( 45,50 ). Interestingly, the molecular mechanism of vorinostat and LB-205, which are both histone deacetylase inhibitors (HDACis), was recently clarifi ed, showing that both compounds inhibit the deacetylation of the middle domain of HSP90, resulting in less recognition of the mutant GCase, and hence less degradation, while increasing the amount of chaperones involved in folding, such as HSPA5 ( 45 ).…”

Section: Proteostasismentioning

confidence: 73%

“…As mentioned above, the potential benefi t of modulation of the HSR is now emerging in the LSD fi eld with the reporting of a number of studies of this approach in genetically distinct diseases such as Gaucher's disease, Tay-Sach's disease, Niemann-Pick disease types A and B, Niemann-Pick disease type C, ␣ -mannosidoses, sialidosis, and mucopolysaccharidosis type 3A ( 7,(43)(44)(45)(46)(47)(48)(49). In cellular studies of Gaucher's and Tay-Sach's disease for example, the induction of the HSR or UPR with celastrol and MG-132 results in increases of both cytosolic and ER-resident chaperones, of the HSP70 family in particular, in a process dependent on UPRresponsive transcription factors Ire1, ATF6, and PERK.…”

Section: Proteostasismentioning

confidence: 99%

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Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Ingemann

Kirkegaard

2014

Journal of Lipid Research

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The lysosomal storage diseases (LSDs) describe a heterogenous family of rare inherited diseases caused by mutations in lysosomal proteins and are characterized by accumulation of macromolecules or monomeric compounds inside organelles of the endo-lysosomal system ( 1-3 ). The LSDs present complex disease phenotypes with the mechanisms leading to pathology being poorly understood, as the disease and extent of pathology seem to depend on the spatiotemporal accumulation of substrates which have a variety of downstream effects depending on their cellular and physiological context ( Table 1 ). It is thus diffi cult to generalize for the LSDs, but as the origin of the diseases in all cases is a genetic lesion, which most often causes a misfolded dysfunctional protein, the cellular processes and responses related to misfolded proteins have to be considered as an integral part of the etiology of any of the diseases. Thus, the shared mechanistic principle of disturbed protein homeostasis and the fact that many LSDs also show an overlap of potentially toxic storage compounds might explain why the LSDs, despite their various monogenetic origins, share a number of cellular and clinical manifestations including perturbed lysosomal traffi cking and autophagy, increased oxidative stress, impaired calcium homeostasis, loss of lysosomal stability, increased Abstract Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defi ned loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a p...

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Section: Proteostasismentioning

confidence: 73%

Section: Proteostasismentioning

confidence: 99%

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Ingemann

Kirkegaard

2014

Journal of Lipid Research

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“…Our previous findings demonstrated that mutations in GCase result in its binding to Hsp90 (18,19). Recognition by Hsp90 initiates protein degradation through the ERAD and valosin-containing protein (VCP)/protein 97 (p97)/ proteasome pathways (7,(19)(20)(21).…”

Section: Celastrol Targets the Chaperone Function Of Hsp90 And Inhibimentioning

confidence: 99%

“…Interfering with the function of Hsp90 has been shown to reduce the degradation of GCase (19). Zhang et al (16) showed that celastrol interferes with Hsp90 function by occupying a specific…”

Section: Celastrol Targets the Chaperone Function Of Hsp90 And Inhibimentioning

confidence: 99%

“…Zhang et al (16,17) showed that celastrol interferes with Hsp90 binding to Hsp90 cochaperone Cdc37 (Cdc37), suggesting that celastrol affects biologic processes by modulating molecular chaperones. Our recent discoveries in GD demonstrated that Hsp90 is not only a critical chaperone that assists protein folding but is also important in targeting the misfolded GCase for degradation (18,19). Therefore, the potential therapeutic value of celastrol is of great interest in protein folding-related disorders.…”

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confidence: 99%

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Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones

Yang

Swallows

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Gaucher disease is caused by mutations in the glucosidase, beta, acid gene that encodes glucocerebrosidase (GCase). Glucosidase, beta, acid mutations often cause protein misfolding and quantitative loss of GCase. In the present study, we found that celastrol, an herb derivative with known anticancer, anti-inflammatory, and antioxidant activity, significantly increased the quantity and catalytic activity of GCase. Celastrol interfered with the establishment of the heat-shock protein 90/Hsp90 cochaperone Cdc37/Hsp90-Hsp70-organizing protein chaperone complex with mutant GCase and reduced heat-shock protein 90-associated protein degradation. In addition, celastrol modulated the expression of molecular chaperones. Bcl2-associated athanogene 3 and heat shock 70kDa proteins 1A and 1B were significantly increased by celastrol. Furthermore, BAG family molecular chaperone regulator 3 assisted protein folding and maturation of mutant GCase. These findings provide insight into a therapeutic strategy for Gaucher disease and other human disorders that are associated with protein misfolding.

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New Directions in Gaucher Disease

et al. 2016

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In Gaucher disease (GD), mutant lysosomal acid β-glucocerebrosidase fails to properly hydrolyze its substrate, glucosylceramide, which accumulates in the lysosomes. Due to its phenotypic heterogeneity, GD has been classified into type 1, non-neuronopathic, and types 2 and 3, the neuronopathic forms, based on the primary involvement of the central nervous system. Neuroinflammation and necroptotic death may appear in the neuronopathic forms of GD, whereas type 1 GD patients may develop Parkinson disease (PD), a prototype of protein misfolding disorders of the nervous system. PD is significantly more prevalent among GD carriers and patients than among the non-GD populations. It is apparent that the amount of mutant enzyme present in lysosomes depends on the amount of mutant enzyme recognized as correctly folded in the endoplasmic reticulum (ER) for physiologically correct transport through the Golgi apparatus to the lysosome. Mutant enzyme recognized as misfolded is retained in the ER, inducing the Unfolded Protein Response. In the current review, we present three discrete areas of interest: molecular and cellular mechanisms underlying the association between GD and PD; the clinical and genetic associations between GD and PD; and treatment options for GD. We also discuss the relevance of induced pleuripotent stem cells to the above associations.

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Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones

Cited by 68 publications

References 38 publications

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones

New Directions in Gaucher Disease

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