Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.

Gaucher disease (GD) is caused by deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase) and the subsequent accumulation of its substrate, glucosylceramide (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) cause GCase misfolding and inhibition of proper lysosomal t...

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Autores principales:	Margarita M Ivanova, Julia Dao, Neil Kasaci, Benjamin Adewale, Shaista Nazari, Lauren Noll, Jacqueline Fikry, Armaghan Hafez Sanati, Ozlem Goker-Alpan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e54339c46bde456e83bae2d7939f71cc
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spelling	oai:doaj.org-article:e54339c46bde456e83bae2d7939f71cc2021-12-02T20:13:31ZCellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.1932-620310.1371/journal.pone.0247211https://doaj.org/article/e54339c46bde456e83bae2d7939f71cc2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0247211https://doaj.org/toc/1932-6203Gaucher disease (GD) is caused by deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase) and the subsequent accumulation of its substrate, glucosylceramide (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) cause GCase misfolding and inhibition of proper lysosomal trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway. GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no direct impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes GC biosynthesis, reducing GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density parallel with the improvement in hematological parameters. We assessed the effects of EGT and AMB on GCase activity and autophagy-lysosomal pathway (ALP) in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. We found that EGT, same as AMB, enhanced GCase activity in control cells and that an individualized response, that varied with GBA mutations, was observed in cells from patients with GD2-3. EGT and AMB enhanced the formation of lysosomal/late endosomal compartments and improved autophagy, independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of mitochondrial function by activating the mitochondrial membrane potential. These results demonstrate that EGT and AMB, with different molecular mechanisms of action, enhance GCase activity and improve autophagy-lysosome dynamics and mitochondrial functions.Margarita M IvanovaJulia DaoNeil KasaciBenjamin AdewaleShaista NazariLauren NollJacqueline FikryArmaghan Hafez SanatiOzlem Goker-AlpanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0247211 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Margarita M Ivanova Julia Dao Neil Kasaci Benjamin Adewale Shaista Nazari Lauren Noll Jacqueline Fikry Armaghan Hafez Sanati Ozlem Goker-Alpan Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
description	Gaucher disease (GD) is caused by deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase) and the subsequent accumulation of its substrate, glucosylceramide (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) cause GCase misfolding and inhibition of proper lysosomal trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway. GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no direct impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes GC biosynthesis, reducing GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density parallel with the improvement in hematological parameters. We assessed the effects of EGT and AMB on GCase activity and autophagy-lysosomal pathway (ALP) in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. We found that EGT, same as AMB, enhanced GCase activity in control cells and that an individualized response, that varied with GBA mutations, was observed in cells from patients with GD2-3. EGT and AMB enhanced the formation of lysosomal/late endosomal compartments and improved autophagy, independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of mitochondrial function by activating the mitochondrial membrane potential. These results demonstrate that EGT and AMB, with different molecular mechanisms of action, enhance GCase activity and improve autophagy-lysosome dynamics and mitochondrial functions.
format	article
author	Margarita M Ivanova Julia Dao Neil Kasaci Benjamin Adewale Shaista Nazari Lauren Noll Jacqueline Fikry Armaghan Hafez Sanati Ozlem Goker-Alpan
author_facet	Margarita M Ivanova Julia Dao Neil Kasaci Benjamin Adewale Shaista Nazari Lauren Noll Jacqueline Fikry Armaghan Hafez Sanati Ozlem Goker-Alpan
author_sort	Margarita M Ivanova
title	Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
title_short	Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
title_full	Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
title_fullStr	Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
title_full_unstemmed	Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.
title_sort	cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic gaucher disease.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/e54339c46bde456e83bae2d7939f71cc
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Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease.

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