Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

作     者：Bagnoli, Enrico Lin, Yu- En Burel, Sophie Jaimon, Ebsy Antico, Odetta Themistokleous, Christos Nikoloff, Jonas M. Squires, Samuel Morella, Ilaria Watzlawik, Jens O. Fiesel, Fabienne C. Springer, Wolfdieter Tonelli, Francesca Lis, Pawel Brooks, Simon P. Dunnett, Stephen B. Brambilla, Riccardo Alessi, Dario R. Pfeffer, Suzanne R. Muqit, Miratul M. K. 

作者机构：Univ Dundee Sch Life Sci MRC Prot Phosphorylat & Ubiquitylat Unit Dundee DD1 5EH Scotland Aligning Sci Parkinsons Collaborat Res Network Chevy Chase MD 20815 USA Stanford Univ Sch Med Dept Biochem Stanford CA 94305 USA Univ Pavia Dept Biol & Biotechnol Lazzaro Spallanzani I-27100 Pavia Italy Cardiff Univ Neurosci & Mental Hlth Innovat Inst Sch Biosci Cardiff CF10 3AX Wales Mayo Clin Dept Neurosci Jacksonville FL 32224 USA Mayo Clin Grad Sch Biomed Sci Neurosci PhD Program Jacksonville FL 32224 USA Cardiff Univ Sch Biosci Div Neurosci Brain Repair Grp Cardiff CF10 3AX Wales 

出 版 物：《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 (Proc. Natl. Acad. Sci. U. S. A.)

年 卷 期：2025年第122卷第5期

页      面：e2412029122页

核心收录：

学科分类：07[理学] 08[工学] 

基　　金：Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit [ASAP-000463] Michael J. Fox Foundation for Parkinson's Research MRC [MR/P00704X/1 COEN] GlaxoSmithKline Merck KGaA Wellcome Trust Senior Research Fellowship in Clinical Science [210753/Z/18/Z] Michael J. Fox Foundation EMBO YIP Award UK MRC [MC_UU_00018/1] MRC Award [MR/S037667/1] University of Dundee School of Life Sciences Summer School Program Mayo Clinic Office of Research Equity, Inclusion and Diversity National Institute of Neurological Disorders and Stroke (NINDS) [RF1NS085070] Mayo Clinic Robert and Arlene Kogod Center on Aging 

主　　题：LRRK2 PINK1 ciliogenesis phosphorylation brain 

摘      要：Mutations in Leucine- rich repeat kinase 2 (LRRK2) and PTEN- induced kinase 1 (PINK1) are associated with familial Parkinson s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock- in mice with PINK1 knock- out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2- mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1- mediated Rab and Ub phosphorylation. In addition, we observe that a pool of up- regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived- neurotrophic factor transcription. This is not exacerbated in double- mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.