Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.

Ilda Coku , Eugénie Mutez (1) , Sabiha Eddarkaoui (2, 1, 3) , Sébastien Carrier (4) , Antoine Marchand (2, 1) , Claire Deldycke , Liesel Goveas (2, 1) , Guillaume Baille (2) , Mélissa Tir (5) , Romain Magnez (2, 6) , Xavier Thuru (4, 6) , Gaëlle Vermeersch , Wim Vandenberghe (7) , Luc Buée (8) , Luc Defebvre (9, 10) , Bernard Sablonnière (1) , Marie-Christine Chartier-Harlin (2, 1) , Jean-Marc Taymans (2, 1) , Vincent Huin (1, 11)

1 LilNCog - Lille Neurosciences & Cognition - U 1172
2 CHU Lille
3 Excellence Laboratory LabEx DISTALZ
4 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
5 LNFP - Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559
6 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
7 INTEC - Department of Information Technology
8 U1172 Inserm - Equipe Alzheimer and Tauopathies - LilNCog
9 Département de neurologie [Lille]
10 NS-Park/FCRIN Network
11 ICM - Institut du Cerveau = Paris Brain Institute

BACKGROUND: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. OBJECTIVES: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. METHODS: We transiently expressed wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293\,T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. RESULTS: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. CONCLUSIONS: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. \textcopyright 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Domaines: Médecine humaine et pathologie

Ilda Coku, Eugénie Mutez, Sabiha Eddarkaoui, Sébastien Carrier, Antoine Marchand, et al.. Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.. Movement Disorders, 2022, ⟨10.1002/mds.29124⟩. ⟨hal-03703786⟩