Publication details

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis

Authors	MILANOWSKI Lukasz M HOU Xu BREDENBERG Jenny M FIESEL Fabienne C COCKER Liam T SOTO-BEASLEY Alexandra I WALTON Ronald L STRONGOSKY Audrey J FAROQI Ayman H BARCIKOWSKA Maria BOCZARSKA-JEDYNAK Magdalena DULSKI Jaroslaw FEDORYSHYN Lyuda JANIK Piotr POTULSKA-CHROMIK Anna KARPINSKY Katherine KRYGOWSKA-WAJS Anna LYNCH Tim OLSZEWSKA Diana A OPALA Grzegorz PULYK Aleksander REKTOROVÁ Irena SANOTSKY Yanosh SIUDA Joanna WIDLAK Mariusz SLAWEK Jaroslaw RUDZINSKA-BAR Monika UITTI Ryan FIGURA Monika SZLUFIK Stanislaw RZONCA-NIEWCZAS Sylwia PODGORSKA Elzbieta MCLEAN Pamela J KOZIOROWSKI Dariusz ROSS Owen A HOFFMAN-ZACHARSKA Dorota SPRINGER Wolfdieter WSZOLEK Zbigniew K
Year of publication	2022
Type	Article in Periodical
Magazine / Source	International Journal of Molecular Sciences
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://www.mdpi.com/1422-0067/23/13/7086
Doi	http://dx.doi.org/10.3390/ijms23137086
Keywords	Parkinson's disease; familial forms; monogenic forms; CTSB; fibroblasts
Description	Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.