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 w...

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Autores: Vela-Desojo L, Pascual A, Montal V, Guerrero C, Osuna-López M, Guallar V, Palau F, Hoenicka J
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p28748
Acesso em linha:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28748
Access Level:acceso abierto
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spelling A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.Vela-Desojo LPascual AMontal VGuerrero COsuna-López MGuallar VPalau FHoenicka JPathogenic 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.NATURE PORTFOLIO2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28748npj Parkinsons DiseaseISSN: 23738057reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p287482026-05-27T12:37:41Z
dc.title.none.fl_str_mv A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
title A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
spellingShingle A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
Vela-Desojo L
title_short A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
title_full A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
title_fullStr A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
title_full_unstemmed A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
title_sort A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.
dc.creator.none.fl_str_mv Vela-Desojo L
Pascual A
Montal V
Guerrero C
Osuna-López M
Guallar V
Palau F
Hoenicka J
author Vela-Desojo L
author_facet Vela-Desojo L
Pascual A
Montal V
Guerrero C
Osuna-López M
Guallar V
Palau F
Hoenicka J
author_role author
author2 Pascual A
Montal V
Guerrero C
Osuna-López M
Guallar V
Palau F
Hoenicka J
author2_role author
author
author
author
author
author
author
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28748
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28748
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv NATURE PORTFOLIO
publisher.none.fl_str_mv NATURE PORTFOLIO
dc.source.none.fl_str_mv npj Parkinsons Disease
ISSN: 23738057
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
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