Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 441, Issue 4, Pages 862-866Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2013.10.159
Keywords
LRRK2; Parkinson's disease; Autophagy; Lysosomes; Signaling pathways
Categories
Funding
- Michael J. Fox Foundation for Parkinson's Research
- Rosetrees Trust
- Parkinson's UK research fellow [F1002]
- Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]
- University of Sheffield
- MRC Protein Phosphorylation Unit at the University of Dundee
- NIHR UCLH BRC
- Cancer Research UK [15153] Funding Source: researchfish
- Medical Research Council [MC_G1000735, G0800437] Funding Source: researchfish
- National Institute for Health Research [CL-2012-21-005, NF-SI-0611-10237] Funding Source: researchfish
- Parkinson's UK [F-1002] Funding Source: researchfish
- MRC [MC_G1000735, G0800437] Funding Source: UKRI
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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. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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