Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Koji Matsuhisa, Kazunori Imaizumi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	endoplasmic reticulum-associated degradation iduronate-2-sulfatase mucopolysaccharidosis type II lysosomal storage disorder Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/29447f80ce6c4340a48594f76e92490b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:29447f80ce6c4340a48594f76e92490b
record_format	dspace
spelling	oai:doaj.org-article:29447f80ce6c4340a48594f76e92490b2021-11-25T17:54:33ZLoss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II10.3390/ijms2222122271422-00671661-6596https://doaj.org/article/29447f80ce6c4340a48594f76e92490b2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12227https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the <i>IDS</i> gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.Koji MatsuhisaKazunori ImaizumiMDPI AGarticleendoplasmic reticulum-associated degradationiduronate-2-sulfatasemucopolysaccharidosis type IIlysosomal storage disorderBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12227, p 12227 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	endoplasmic reticulum-associated degradation iduronate-2-sulfatase mucopolysaccharidosis type II lysosomal storage disorder Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	endoplasmic reticulum-associated degradation iduronate-2-sulfatase mucopolysaccharidosis type II lysosomal storage disorder Biology (General) QH301-705.5 Chemistry QD1-999 Koji Matsuhisa Kazunori Imaizumi Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
description	Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the <i>IDS</i> gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.
format	article
author	Koji Matsuhisa Kazunori Imaizumi
author_facet	Koji Matsuhisa Kazunori Imaizumi
author_sort	Koji Matsuhisa
title	Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
title_short	Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
title_full	Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
title_fullStr	Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
title_full_unstemmed	Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
title_sort	loss of function of mutant ids due to endoplasmic reticulum-associated degradation: new therapeutic opportunities for mucopolysaccharidosis type ii
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/29447f80ce6c4340a48594f76e92490b
work_keys_str_mv	AT kojimatsuhisa lossoffunctionofmutantidsduetoendoplasmicreticulumassociateddegradationnewtherapeuticopportunitiesformucopolysaccharidosistypeii AT kazunoriimaizumi lossoffunctionofmutantidsduetoendoplasmicreticulumassociateddegradationnewtherapeuticopportunitiesformucopolysaccharidosistypeii
_version_	1718411853347946496

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Ejemplares similares