Proteomics analysis of the brain from a Gaucher disease mouse identifies pathological pathways including a possible role for transglutaminase 1.
Gaucher disease
RNAseq
glucosylceramide
pathogenesis
proteomics
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
10 Dec 2023
10 Dec 2023
Historique:
revised:
22
10
2023
received:
06
06
2023
accepted:
14
11
2023
medline:
10
12
2023
pubmed:
10
12
2023
entrez:
10
12
2023
Statut:
aheadofprint
Résumé
Gaucher disease (GD) is a lysosomal storage disorder (LSD) caused by the defective activity of acid β-glucosidase (GCase) which results from mutations in GBA1. Neurological forms of GD (nGD) can be generated in mice by intra-peritoneal injection of conduritol B-epoxide (CBE) which irreversibly inhibits GCase. Using this approach, a number of pathological pathways have been identified in mouse brain by RNAseq. However, unlike transcriptomics, proteomics gives direct information about protein expression which is more likely to provide insight into which cellular pathways are impacted in disease. We now perform non-targeted, mass spectrometry-based quantitative proteomics on brains from mice injected with 50 mg/kg body weight CBE for 13 days. Of the 5038 detected proteins, 472 were differentially expressed between control and CBE-injected mice of which 104 were selected for further analysis based on higher stringency criteria. We also compared these proteins with differentially expressed genes (DEGs) identified by RNAseq. Some lysosomal proteins were up-regulated as was interferon signaling, whereas levels of ion channel related proteins and some proteins associated with neurotransmitter signaling were reduced, as was cholesterol metabolism. One protein, transglutaminase 1 (TGM1), which is elevated in a number of neurodegenerative diseases, was absent from the control group but was found at high levels in CBE-injected mice, and located in the extracellular matrix (ECM) in layer V of the cortex and intracellularly in Purkinje cells in the cerebellum. Together, the proteomics data confirm previous RNAseq data and add additional mechanistic understanding about cellular pathways that may play a role in nGD pathology.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Children's Gaucher Research Fund
Organisme : Genzyme-Sanofi
Informations de copyright
© 2023 International Society for Neurochemistry.
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