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Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

Manzoni, C; Mamais, A; Dihanich, S; McGoldrick, P; Devine, MJ; Zerle, J; Kara, E; ... Lewis, PA; + view all (2013) Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochemical and Biophysical Research Communications , 441 (4) pp. 862-866. 10.1016/j.bbrc.2013.10.159. Green open access

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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.

Type: Article
Title: Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbrc.2013.10.159
Publisher version: http://dx.doi.org/10.1016/j.bbrc.2013.10.159
Language: English
Additional information: © 2013 The Authors. Published by Elsevier Inc. Open acces under CC BY licence.
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, Autophagy, Catalytic Domain, Cell Culture Techniques, Female, Fibroblasts, Genetic Markers, Humans, Lysosomes, Male, Microtubule-Associated Proteins, Parkinson Disease, Point Mutation, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1414671
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