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, M. J., Zerle, J., Kara, E., Taanman, J.-W., Healy, D. G., Marti-Masso, J.-F., Schapira, A. H., Plun-Favreau, H., Tooze, S., Hardy, J., Bandopadhyay, R. and Lewis, P. A. (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. ISSN 0006-291X doi: 10.1016/j.bbrc.2013.10.159

Abstract/Summary

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 consis- tently 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 high- light 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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/37258
Item Type	Article
Refereed	Yes
Divisions	Interdisciplinary Research Centres (IDRCs) > Centre for Integrative Neuroscience and Neurodynamics (CINN) Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Uncontrolled Keywords	LRRK2; Parkinson’s disease; Autophagy; Lysosomes; Signaling pathways
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