A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A

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.