A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A
Por:
Vela-Desojo L, Pascual-Rodriguez A, Montal V, Guerrero C, Osuna-Lopez M, Guallar V, Palau F and Hoenicka J
Publicada:
7 jun 2025
Ahead of Print:
7 jun 2025
Resumen:
Pathogenic variants in the LRRK2 gene affecting catalytic domains are the most common genetic cause of Parkinson's disease (PD). Nevertheless, LRRK2 variants at the armadillo (ARM) domain would indirectly affect the protein's activity by interacting with RAB proteins. We present a family with PD recurrence segregating the new LRRK2 allele at the ARM domain, p.[Leu.119Pro;Leu488Pro]. Clinical exams were conducted on nine relatives. Neuropathology of the index case showed loss of substantia nigra neurons and Alzheimer's disease-type lesions. In silico analysis of the p.[Leu.119Pro;Leu488Pro] LRRK2 variant predicted alterations in ARM tertiary structure and binding affinity. These predictions were supported by functional genomics using recombinant LRRK2(WT) and LRRK2(Leu119Pro;Leu488Pro). We found increased interaction between LRRK2(Leu119Pro;Leu488Pro) and RAB8A, but not with RAB10. Additionally, docking studies revealed stronger affinity of LRRK2(Leu119Pro;Leu488Pro) for RAB8A (P < 0.0001) and allosteric properties beyond the mutated residues. We propose p.[Leu119Pro;Leu488Pro] as a cause of familial PD.
Filiaciones:
Vela-Desojo L:
Movement Disorders Unit, Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
Pascual-Rodriguez A:
Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
Montal V:
Barcelona Supercomputing Center, Barcelona, Spain
Guerrero C:
Department of Pathology, Hospital Fundación Alcorcon, Madrid, Spain
Osuna-Lopez M:
Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Guallar V:
Barcelona Supercomputing Center, Barcelona, Spain
Nostrum Biodiscovery, Barcelona, Spain
Palau F:
Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
Únicas SJD, Hospital Sant Joan de Déu, Barcelona, Spain
Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain
Hoenicka J:
Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
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