Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells

Show full item record



Permalink

http://hdl.handle.net/10138/307690

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

Title: Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells
Author: Hanemaaijer, Evelyn S.; Panahi, Mahmod; Swaddiwudhipong, Nol; Tikka, Saara; Winblad, Bengt; Viitanen, Matti; Piras, Antonio; Behbahani, Homira
Contributor: University of Helsinki, Department of Biochemistry and Developmental Biology
Date: 2018-11
Language: eng
Number of pages: 11
Belongs to series: European Journal of Cell Biology
ISSN: 0171-9335
URI: http://hdl.handle.net/10138/307690
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.
Subject: VSMC
LC3
Lysosomes
CADASIL
Autophagy
AUTOSOMAL-DOMINANT ARTERIOPATHY
SUBCORTICAL INFARCTS
NOTCH3 MUTATIONS
INHIBITION
EXPRESSION
UBIQUITIN
DEGRADATION
CHLOROQUINE
P62/SQSTM1
ACTIVATION
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
1_s2.0_S0171933518300815_main.pdf 2.578Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record