Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease.
1-Deoxynojirimycin
/ analogs & derivatives
Biomarkers
/ metabolism
Endoplasmic Reticulum
/ genetics
Fabry Disease
/ drug therapy
Fibroblasts
/ drug effects
Gene Expression Regulation, Enzymologic
/ drug effects
Humans
Lysosomal Storage Diseases
/ drug therapy
Lysosomes
/ enzymology
Mutation, Missense
/ genetics
Proteasome Endopeptidase Complex
/ genetics
Protein Transport
/ drug effects
Proteostasis
/ genetics
Sphingosine
/ analogs & derivatives
alpha-Galactosidase
/ genetics
globotriaosylsphingosine
lysosomal enzyme
proteasome inhibitor
protein misfolding
transcriptomics
Journal
The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R
Informations de publication
Date de publication:
31 01 2020
31 01 2020
Historique:
received:
17
07
2019
revised:
17
12
2019
accepted:
02
01
2020
pubmed:
4
1
2020
medline:
1
7
2020
entrez:
4
1
2020
Statut:
ppublish
Résumé
The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.
Identifiants
pubmed: 31899485
pii: 221764
doi: 10.1042/BCJ20190513
pmc: PMC6993862
doi:
Substances chimiques
Biomarkers
0
1-Deoxynojirimycin
19130-96-2
migalastat
C4XNY919FW
alpha-Galactosidase
EC 3.2.1.22
Proteasome Endopeptidase Complex
EC 3.4.25.1
Sphingosine
NGZ37HRE42
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
359-380Informations de copyright
© 2020 The Author(s).
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