Heather Mortiboys1, Rebecca Furmston1, Gunnar Bronstad1, Jan Aasly1, Chris Elliott1, Oliver Bandmann2. 1. From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway. 2. From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway. o.bandmann@sheffield.ac.uk.
Abstract
OBJECTIVE: To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo. METHODS: Intracellular adenosine 5'-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M-LRRK2(G2019S), NM-LRRK2(G2019S), and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2(G2019S) and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2(G2019S). RESULTS: Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2(G2019S) and NM-LRRK2(G2019S) with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2(G2019) and rescued the loss of visual function in LRRK2(G2019S) flies. CONCLUSION: There is clear preclinical impairment of mitochondrial function in NM-LRRK2(G2019S) that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2(G2019S) and M-LRRK2(G2019S) as well as on the function of dopaminergic neurons expressing LRRK2(G2019S) suggests that UDCA is a promising drug for future neuroprotective trials.
OBJECTIVE: To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo. METHODS: Intracellular adenosine 5'-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M-LRRK2(G2019S), NM-LRRK2(G2019S), and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2(G2019S) and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2(G2019S). RESULTS: Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2(G2019S) and NM-LRRK2(G2019S) with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2(G2019) and rescued the loss of visual function in LRRK2(G2019S) flies. CONCLUSION: There is clear preclinical impairment of mitochondrial function in NM-LRRK2(G2019S) that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2(G2019S) and M-LRRK2(G2019S) as well as on the function of dopaminergic neurons expressing LRRK2(G2019S) suggests that UDCA is a promising drug for future neuroprotective trials.
Authors: Hans-Hermann Hoepken; Suzana Gispert; Blas Morales; Oliver Wingerter; Domenico Del Turco; Alexander Mülsch; Robert L Nussbaum; Klaus Müller; Stefan Dröse; Ulrich Brandt; Thomas Deller; Brunhilde Wirth; Alexei P Kudin; Wolfram S Kunz; Georg Auburger Journal: Neurobiol Dis Date: 2006-11-30 Impact factor: 5.996
Authors: Wanli W Smith; Zhong Pei; Haibing Jiang; Valina L Dawson; Ted M Dawson; Christopher A Ross Journal: Nat Neurosci Date: 2006-09-17 Impact factor: 24.884
Authors: Anne Grünewald; Björn Arns; Britta Meier; Kathrin Brockmann; Vera Tadic; Christine Klein Journal: Antioxid Redox Signal Date: 2014-03-07 Impact factor: 8.401
Authors: Wanli W Smith; Zhong Pei; Haibing Jiang; Darren J Moore; Yideng Liang; Andrew B West; Valina L Dawson; Ted M Dawson; Christopher A Ross Journal: Proc Natl Acad Sci U S A Date: 2005-12-13 Impact factor: 11.205
Authors: Daniel G Healy; Mario Falchi; Sean S O'Sullivan; Vincenzo Bonifati; Alexandra Durr; Susan Bressman; Alexis Brice; Jan Aasly; Cyrus P Zabetian; Stefano Goldwurm; Joaquim J Ferreira; Eduardo Tolosa; Denise M Kay; Christine Klein; David R Williams; Connie Marras; Anthony E Lang; Zbigniew K Wszolek; Jose Berciano; Anthony H V Schapira; Timothy Lynch; Kailash P Bhatia; Thomas Gasser; Andrew J Lees; Nicholas W Wood Journal: Lancet Neurol Date: 2008-06-06 Impact factor: 44.182
Authors: Elisa Greggio; Shushant Jain; Ann Kingsbury; Rina Bandopadhyay; Patrick Lewis; Alice Kaganovich; Marcel P van der Brug; Alexandra Beilina; Jeff Blackinton; Kelly Jean Thomas; Rili Ahmad; David W Miller; Sashi Kesavapany; Andrew Singleton; Andrew Lees; Robert J Harvey; Kirsten Harvey; Mark R Cookson Journal: Neurobiol Dis Date: 2006-06-05 Impact factor: 5.996
Authors: Farinaz Afsari; Kenneth V Christensen; Garrick Paul Smith; Morten Hentzer; Olivia M Nippe; Christopher J H Elliott; Alex R Wade Journal: Hum Mol Genet Date: 2014-04-09 Impact factor: 6.150
Authors: Heather Mortiboys; Kelly Jean Thomas; Werner J H Koopman; Stefanie Klaffke; Patrick Abou-Sleiman; Simon Olpin; Nicholas W Wood; Peter H G M Willems; Jan A M Smeitink; Mark R Cookson; Oliver Bandmann Journal: Ann Neurol Date: 2008-11 Impact factor: 10.422
Authors: Abhishek G Sathe; Paul Tuite; Chi Chen; Yiwei Ma; Wei Chen; James Cloyd; Walter C Low; Clifford J Steer; Byeong-Yeul Lee; Xiao-Hong Zhu; Lisa D Coles Journal: J Clin Pharmacol Date: 2020-02-12 Impact factor: 3.126
Authors: Bruno L Santos-Lobato; Luiz Gustavo Gardinassi; Mariza Bortolanza; Ana Paula Ferranti Peti; Ângela V Pimentel; Lúcia Helena Faccioli; Elaine A Del-Bel; Vitor Tumas Journal: Mol Neurobiol Date: 2021-12-02 Impact factor: 5.590
Authors: Pavan Bhargava; Matthew D Smith; Leah Mische; Emily Harrington; Kathryn C Fitzgerald; Kyle Martin; Sol Kim; Arthur Anthony Reyes; Jaime Gonzalez-Cardona; Christina Volsko; Ajai Tripathi; Sonal Singh; Kesava Varanasi; Hannah-Noelle Lord; Keya Meyers; Michelle Taylor; Marjan Gharagozloo; Elias S Sotirchos; Bardia Nourbakhsh; Ranjan Dutta; Ellen M Mowry; Emmanuelle Waubant; Peter A Calabresi Journal: J Clin Invest Date: 2020-07-01 Impact factor: 14.808