title: The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity.
abstract: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common known cause of Parkinson's disease (PD). The clinical features of LRRK2 PD are indistinguishable from idiopathic PD, with accumulation of α-synuclein and/or tau and/or ubiquitin in intraneuronal aggregates. This suggests that LRRK2 is a key to understanding the aetiology of the disorder. Although loss-of-function does not appear to be the mechanism causing PD in LRRK2 patients, it is not clear how this protein mediates toxicity. In this study, we report that LRRK2 overexpression in cells and in vivo impairs the activity of the ubiquitin-proteasome pathway, and that this accounts for the accumulation of diverse substrates with LRRK2 overexpression. We show that this is not mediated by large LRRK2 aggregates or sequestration of ubiquitin to the aggregates. Importantly, such abnormalities are not seen with overexpression of the related protein LRRK1. Our data suggest that LRRK2 inhibits the clearance of proteasome substrates upstream of proteasome catalytic activity, favouring the accumulation of proteins and aggregate formation. Thus, we provide a molecular link between LRRK2, the most common known cause of PD, and its previously described phenotype of protein accumulation.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: M
authors.initials: M
authors.lastname: Lichtenberg
authors.forename: A
authors.initials: A
authors.lastname: Mansilla
authors.forename: V R
authors.initials: VR
authors.lastname: Zecchini
authors.forename: A
authors.initials: A
authors.lastname: Fleming
authors.forename: D C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D055162:Biocatalysis; D002460:Cell Line; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D023421:Models, Animal; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D015027:Zebrafish; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex