title: Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation.
abstract: LRRK2 is one of the most important genetic contributors to Parkinson's disease (PD). Point mutations in this gene cause an autosomal dominant form of PD, but to date no cellular phenotype has been consistently linked with mutations in each of the functional domains (ROC, COR and Kinase) of the protein product of this gene. In this study, primary fibroblasts from individuals carrying pathogenic mutations in the three central domains of LRRK2 were assessed for alterations in the autophagy/lysosomal pathway using a combination of biochemical and cellular approaches. Mutations in all three domains resulted in alterations in markers for autophagy/lysosomal function compared to wild type cells. These data highlight the autophagy and lysosomal pathways as read outs for pathogenic LRRK2 function and as a marker for disease, and provide insight into the mechanisms linking LRRK2 function and mutations.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Electronic address: c.manzoni@ucl.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.forename: Sybille
authors.initials: S
authors.lastname: Dihanich
authors.forename: Phillip
authors.initials: P
authors.lastname: McGoldrick
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devine
authors.forename: Julia
authors.initials: J
authors.lastname: Zerle
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Healy
authors.forename: Jose-Felix
authors.initials: JF
authors.lastname: Marti-Masso
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Schapira
authors.forename: Helene
authors.initials: H
authors.lastname: Plun-Favreau
authors.forename: Sharon
authors.initials: S
authors.lastname: Tooze
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
mesh_terms: D001343:Autophagy / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D018929:Cell Culture Techniques; D005260:Female; D005347:Fibroblasts; D005819:Genetic Markers; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: D005819:Genetic Markers; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Autophagy; C-terminal of ROC; COR; ICC; Immunocytochemistry; LRRK2; Lysosomes; PD; Parkinson’s disease; ROC; Signaling pathways; leucine rich repeat kinase 2; ras of complex proteins