Improved intracellular delivery of glucocerebrosidase mediated by the HIV-1 TAT protein transduction domain

Lee, Kyun Oh; Luu, Nga; Kaneski, Christine R.; Schiffmann, Raphael; Brady, Roscoe O.; Murray, Gary J.

doi:10.1016/j.bbrc.2005.05.207

Cited by 36 publications

(38 citation statements)

References 23 publications

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“…One approach might be to add a protein transduction domain such as the 11-amino acid TAT peptide. [28] Such an approach had led to a widespread tissue distribution of intravenously infused TAT-β-galactosidase [29]. Kidney -A. Agalsidase alfa injected mouse shows immunoreactivity in cortical tubule cytoplasm (arrows).…”

Section: Discussionmentioning

confidence: 99%

Cellular and tissue distribution of intravenously administered agalsidase alfa

Murray

Anver

Kennedy

et al. 2007

Molecular Genetics and Metabolism

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Abstractα-Galactosidase A is the lysosomal hydrolase that is deficient in patients with Fabry disease. Intravenous infusion of agalsidase alfa, a preparation of α-galactosidase A, is used for enzyme replacement therapy (ERT) in patients with Fabry disease. Although ERT appears to show some beneficial effects, most patients show only a modest response. We investigated using immunohistochemistry the relative tissue and cellular distribution of agalsidase alfa after a single intravenous injection in a mouse knockout model of Fabry disease. Specific immunostaining for agalsidase alfa was found only in liver, kidney, heart, testes, adrenal gland, spleen and bone marrow. There was no difference in distribution of the infused enzyme distribution among tissues sampled 4, 24, and 48 hours post-injection. The intracellular localization of immunopositivity varied considerably between organs with vascular endothelium being the most commonly positive site. α-Galactosidase A specific activity in tissue homogenates matched the relative extent of agalsidase alfa immunostaining distribution in the same organs. We conclude that intravenously injected agalsidase alfa has a very heterogeneous systemic distribution using an immunostaining technique.

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Section: Discussionmentioning

confidence: 99%

Cellular and tissue distribution of intravenously administered agalsidase alfa

Murray

Anver

Kennedy

et al. 2007

Molecular Genetics and Metabolism

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“…The fluorometric GCase enzyme activity assay was performed as described previously (38). In brief, 1 million cells were pelleted and flash-frozen on dry ice.…”

Section: Methodsmentioning

confidence: 99%

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

Yang

Rahimpour

Lü

et al. 2012

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

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Gaucher disease is caused by mutations of the GBA gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations often result in protein misfolding and premature degradation, but usually exert less effect on catalytic activity. In this study, we identified the molecular mechanism by which histone deacetylase inhibitors increase the quantity and activity of GCase. Specifically, these inhibitors limit the deacetylation of heat shock protein 90, resulting in less recognition of the mutant peptide and GCase degradation. These findings provide insight into a possible therapeutic strategy for Gaucher disease and other genetic disorders by modifying molecular chaperone and protein degradation pathways.

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“…The TAT domain efficiently delivers cargo molecules to the cytoplasm in a wide range of species, including human. 27 A peptide comprising His-TAT-NLS domains was used as control. When neurons were exposed to His-TAT-REST5 (REST5) peptides, the peptide was detected in nuclear extracts within 2 h and accumulation increased through 4 h, slowly decreasing thereafter (Figure 4a).…”

Section: Kolev Et Almentioning

confidence: 99%

Upregulating CD59: a new strategy for protection of neurons from complement-mediated degeneration

et al. 2009

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An increasing number of studies have shown a critical role for the membrane attack complex, synthesized on activation of the terminal pathway of the complement system, in causing demyelination and neuronal death in neurodegeneration. The aim of this study was to develop a strategy to increase the resistance of neurons to complement damage by modulating the expression of membrane complement regulatory protein CD59, the only inhibitor of the terminal pathway of the complement cascade. We exploited our recent finding that CD59 expression is regulated by the neural-restrictive silencer factor (REST) and designed a novel REST-derived peptide (REST5) containing the nuclear localization domain of the wild-type protein. The effect of REST5 and the mechanism by which it modulates CD59 expression were modelled in neuroblastoma cells transfected with expression constructs, and then confirmed in human neurons differentiated from neural progenitor cells. REST5 increased the expression of CD59 in neurons by fivefold and protected them from complement-mediated lysis spontaneously triggered by neurons. As a source of complement, we used either human serum or conditioned medium from primary human oligodendroglia. This study brings new insight into immunopharmacological research that may serve to inhibit neuronal death triggered by the terminal pathway of complement activation.

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Improved intracellular delivery of glucocerebrosidase mediated by the HIV-1 TAT protein transduction domain

Cited by 36 publications

References 23 publications

Cellular and tissue distribution of intravenously administered agalsidase alfa

Cellular and tissue distribution of intravenously administered agalsidase alfa

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

Upregulating CD59: a new strategy for protection of neurons from complement-mediated degeneration

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