Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells

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dc.contributor.author Hanemaaijer, Evelyn S.
dc.contributor.author Panahi, Mahmod
dc.contributor.author Swaddiwudhipong, Nol
dc.contributor.author Tikka, Saara
dc.contributor.author Winblad, Bengt
dc.contributor.author Viitanen, Matti
dc.contributor.author Piras, Antonio
dc.contributor.author Behbahani, Homira
dc.date.accessioned 2019-11-29T23:00:05Z
dc.date.available 2021-12-17T22:45:29Z
dc.date.issued 2018-11
dc.identifier.citation Hanemaaijer , E S , Panahi , M , Swaddiwudhipong , N , Tikka , S , Winblad , B , Viitanen , M , Piras , A & Behbahani , H 2018 , ' Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells ' , European Journal of Cell Biology , vol. 97 , no. 8 , pp. 557-567 . https://doi.org/10.1016/j.ejcb.2018.10.001
dc.identifier.other PURE: 122551344
dc.identifier.other PURE UUID: 362d1b30-9046-4f19-90f2-c62f49ae7de1
dc.identifier.other WOS: 000457068600004
dc.identifier.other Scopus: 85055905305
dc.identifier.uri http://hdl.handle.net/10138/307690
dc.description.abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial progressive degenerative disorder and is caused by mutations in NOTCH3 gene. Previous study reported that mutant NOTCH3 is more prone to form aggregates than wild-type NOTCH3 and the mutant aggregates are resistant to degradation. We hypothesized that aggregation or accumulation of NOTCH3 could be due to impaired lysosomal-autophagy machinery in VSMC. Here, we investigated the possible cause of accumulation/aggregation of NOTCH3 in CADASIL using cerebral VSMCs derived from control and CADASIL patients carrying NOTCH3(RI33C) mutation. Thioflavin-S-staining confirmed the increased accumulation of aggregated NOTCH3 in VSMCR133C compared to VSMCWT. Increased levels of the lysosomal marker, Lamp2, were detected in VSMCR133C, which also showed co-localization with NOTCH3 using double-immunohistochemistry. Increased level of LC3-II/LC3-I ratio was observed in VSMCR133C suggesting an accumulation of autophagosomes. This was coupled with the decreased co-localization of NOTCH3 with LC3, and Lamp2 and, further, increase of p62/SQSTM1 levels in VSMCR133C compared to the VSMCWT. In addition, Western blot analysis indicated phosphorylation of p-ERK, p-S6RP, and p-P70 S6K. Altogether, these results suggested a dysfunction in the autophagy-lysosomal pathway in VSMCR133C. The present study provides an interesting avenue of the research investigating the molecular mechanism of CADASIL. en
dc.format.extent 11
dc.language.iso eng
dc.relation.ispartof European Journal of Cell Biology
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject VSMC
dc.subject LC3
dc.subject Lysosomes
dc.subject CADASIL
dc.subject Autophagy
dc.subject AUTOSOMAL-DOMINANT ARTERIOPATHY
dc.subject SUBCORTICAL INFARCTS
dc.subject NOTCH3 MUTATIONS
dc.subject INHIBITION
dc.subject EXPRESSION
dc.subject UBIQUITIN
dc.subject DEGRADATION
dc.subject CHLOROQUINE
dc.subject P62/SQSTM1
dc.subject ACTIVATION
dc.subject 3111 Biomedicine
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells en
dc.type Article
dc.contributor.organization Department of Biochemistry and Developmental Biology
dc.contributor.organization Medicum
dc.contributor.organization University of Helsinki
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.ejcb.2018.10.001
dc.relation.issn 0171-9335
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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