AUTHOR=Smith Laura J. , Lee Chiao-Yin , Menozzi Elisa , Schapira Anthony H. V. 

TITLE=Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease

JOURNAL=Frontiers in Neurology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.971252

DOI=10.3389/fneur.2022.971252

ISSN=1664-2295

ABSTRACT=<p>Variants in the <italic>GBA1</italic> and <italic>LRRK2</italic> genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the <italic>GBA1</italic> gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the <italic>LRRK2</italic> gene encoding for the leucine-rich repeat kinase 2 enzyme. <italic>GBA1</italic>-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the <italic>GBA1</italic> gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for <italic>GBA1</italic> variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, <italic>LRRK2</italic>-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the <italic>LRRK2</italic> gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of <italic>GBA1</italic> and <italic>LRRK2</italic> pathways, with double mutant carriers showing a milder phenotype compared to <italic>GBA1</italic>-associated PD. This review compares <italic>GBA1</italic> and <italic>LRRK2</italic>-associated PD, and highlights possible genotype-phenotype associations for <italic>GBA1</italic> and <italic>LRRK2</italic> separately, based on biochemical consequences of single variants.</p>