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

Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the...

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Autores principales: Smith, Laura J., Lee, Chiao-Yin, Menozzi, Elisa, Schapira, Anthony H. V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9416236/
https://www.ncbi.nlm.nih.gov/pubmed/36034282
http://dx.doi.org/10.3389/fneur.2022.971252
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author Smith, Laura J.
Lee, Chiao-Yin
Menozzi, Elisa
Schapira, Anthony H. V.
author_facet Smith, Laura J.
Lee, Chiao-Yin
Menozzi, Elisa
Schapira, Anthony H. V.
author_sort Smith, Laura J.
collection PubMed
description Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 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 GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.
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spelling pubmed-94162362022-08-27 Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease Smith, Laura J. Lee, Chiao-Yin Menozzi, Elisa Schapira, Anthony H. V. Front Neurol Neurology Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 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 GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants. Frontiers Media S.A. 2022-08-12 /pmc/articles/PMC9416236/ /pubmed/36034282 http://dx.doi.org/10.3389/fneur.2022.971252 Text en Copyright © 2022 Smith, Lee, Menozzi and Schapira. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Smith, Laura J.
Lee, Chiao-Yin
Menozzi, Elisa
Schapira, Anthony H. V.
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title_full Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title_fullStr Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title_full_unstemmed Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title_short Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
title_sort genetic variations in gba1 and lrrk2 genes: biochemical and clinical consequences in parkinson disease
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9416236/
https://www.ncbi.nlm.nih.gov/pubmed/36034282
http://dx.doi.org/10.3389/fneur.2022.971252
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