@article{536d83c7a6b34d159aec189692e232f5,
title = "Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers",
abstract = "Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-Associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-Associated Parkinson's disease brain.",
keywords = "LRRK2, Parkinson's disease, alpha-synuclein, kinase inhibitor, retromer",
author = "Ye Zhao and Gayathri Perera and Junko Takahashi-Fujigasaki and Mash, {Deborah C.} and Vonsattel, {Jean Paul G.} and Akiko Uchino and Kazuko Hasegawa and {Jeremy Nichols}, R. and Holton, {Janice L.} and Shigeo Murayama and Nicolas Dzamko and Halliday, {Glenda M.}",
note = "Funding Information: This work was supported by a research grant jointly funded by the Michael J Fox Foundation for Parkinson{\textquoteright}s Disease Research and the Shake It Up Australia Foundation (awarded to G.M.H., N.D., S.M., R.J.N. and J.L.H.) and by a Parkinson{\textquoteright}s New South Wales seed grant awarded to ND. YZ holds a scholarship from the University of New South Wales and an Elizabeth-Gilbert Scholarship from Neuroscience Research Australia. G.M.H. holds a senior principal research fellowship from the National Health and Medical Research Council of Australia (#1079679). J.L.H. is supported by the Multiple System Atrophy Trust, Alzheimer{\textquoteright}s Research UK. Tissues received from the Sydney Brain Bank at Neuroscience Research Australia were collected with funding from the University of New South Wales and Neuroscience Research Australia. Queen Square Brain Bank is supported by Reta Lila Weston Institute for Neurological Studies and the Medical Research Council UK. The University of Miami Brain Endowment Bank USA is a National Institutes of Health funded NeuroBioBank funded by contract support provided by the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the National Institute of Child Health and Development. LRRK2 autopsy collection at Columbia University was funded by the Parkinson{\textquoteright}s Disease Foundation and the Michael J Fox Foundation.",
year = "2018",
month = feb,
day = "1",
doi = "10.1093/brain/awx344",
language = "English (US)",
volume = "141",
pages = "486--495",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "2",
}