pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

Mena‐Barragán, Teresa; Narita, Aya; Matias, Dino; Tiscórnia, Gustavo; Nanba, Eiji; Ohno, Kousaku; Suzuki, Yoshiyuki; Higaki, Kazutaka; García-Fernández, José Manuel; Mellet, Carmen Ortiz

doi:10.1002/anie.201505147

Cited by 63 publications

(46 citation statements)

References 37 publications

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“…The finding that PGRN acts as a co-chaperone of HSP70 and is required for disaggregation of GCase, together with the facts that chaperone-based treatments aiming to enhance GCase lysosomal localization have proven to be a promising alternative to enzyme replacement treatment (ERT) and substrate reduction therapy (SRT) for GD (Zimran et al, 2013, Sanchez-Fernandez et al, 2016, Jung et al, 2016, Mena-Barragan et al, 2015), and recombinant HSP70 has been shown to effectively correct altered lysosomal stability seen in Niemann–Pick B disease (NPD) (Kirkegaard et al, 2010), promoted us to examine whether PGRN would have therapeutic effects in GD. Indeed, we have found that recombinant PGRN protein is therapeutic against Gaucher disease (Jian et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

et al. 2016

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Gaucher disease (GD), the most common lysosomal storage disease, is caused by mutations in GBA1 encoding of β-glucocerebrosidase (GCase). Recently it was reported that progranulin (PGRN) insufficiency and deficiency associated with GD in human and mice, respectively. However the underlying mechanisms remain unknown. Here we report that PGRN binds directly to GCase and its deficiency results in aggregation of GCase and its receptor LIMP2. Mass spectrometry approaches identified HSP70 as a GCase/LIMP2 complex-associated protein upon stress, with PGRN as an indispensable adaptor. Additionally, 98 amino acids of C-terminal PGRN, referred to as Pcgin, are required and sufficient for the binding to GCase and HSP70. Pcgin effectively ameliorates the disease phenotype in GD patient fibroblasts and animal models. These findings not only demonstrate that PGRN is a co-chaperone of HSP70 and plays an important role in GCase lysosomal localization, but may also provide new therapeutic interventions for lysosomal storage diseases, in particular GD.

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Section: Resultsmentioning

confidence: 99%

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

et al. 2016

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“…Most of these molecules target the active site and must therefore be reversible inhibitors, ideally with shorter half-lives that the substrate, but compounds that interact with other regions of the protein could in principle also work. Recently, pH sensitive chaperones have been developed which bind strongly to the GCase active site at neutral pH but lose affinity when exposed to the lower pH found in the lysosome [25]. While some chaperones have reached human clinical trials, to date none has shown any significant improvement in clinical outcome.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

Santos

Tiscórnia

2017

IJMS

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Gaucher’s disease (GD) is the most frequently inherited lysosomal storage disease, presenting both visceral and neurologic symptoms. Mutations in acid β-glucocerebrosidase disrupt the sphingolipid catabolic pathway promoting glucosylceramide (GlcCer) accumulation in lysosomes. Current treatment options are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, neither of these approaches is effective in treating the neurological aspect of the disease. The use of small pharmacological compounds that act as molecular chaperones is a promising approach that is still experimental. In recent years, an association between GD and Parkinson like synucleinopathies has been discovered. Since 1992, a number of mouse models of GD have been the developed and partially reproduce phenotype of the disease. More recently, the discovery of direct reprograming has allowed the derivation of induced pluripotent stem cells (iPSc) from fibroblasts obtained from GD patients. iPSc can be expanded indefinitely in vitro and differentiated to macrophages and neurons, the main relevant cell types involved in GD. In this work, we review iPSc models of GD and summarize what we have learned from this system.

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“…It would be useful to find molecules that bind and stabilize AGAL mutants when they are in the neutral environment of the endoplasmic reticulum, but dissociate when the protein reaches the lysosome. This point was specifically addressed incorporating an orthoester segment into DGJ [93]. …”

Section: Future Perspectives For Therapymentioning

confidence: 99%

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

Citro

Cammisa

Liguori

et al. 2016

IJMS

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Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants.

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pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

Cited by 63 publications

References 37 publications

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

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