title: LRRK2 Promotes Tau Accumulation, Aggregation and Release.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD.
authors.affiliation: Instituto de Medicina Molecular, 1649-028, Lisbon, Portugal.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Patrícia Silva
authors.initials: PS
authors.lastname: Guerreiro
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Instituto de Medicina Molecular, 1649-028, Lisbon, Portugal.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Tomás
authors.initials: T
authors.lastname: Lopes da Fonseca
authors.affiliation: Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.affiliation: Instituto de Medicina Molecular, 1649-028, Lisbon, Portugal. touteir@gwdg.de.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany. touteir@gwdg.de.|Department of Neurodegeneration and Restorative Research, University Medical Center Goettingen, Waldweg 33, 37073, Goettingen, Germany. touteir@gwdg.de.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Eckermann
mesh_terms: D001343:Autophagy; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism*; D008954:Models, Biological; D008970:Molecular Weight; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding; D059748:Proteolysis; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D016875:tau Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D046988:Proteasome Endopeptidase Complex
keywords: LRRK2; Protein accumulation; Protein degradation; Tau