This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Objective: To further characterize mitochondrial dysfunction in LRRK2G2019S mutant Parkinson disease (PD) patient tissue (M-LRRK2G2019S), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2G2019S mutation carriers (NM-LRRK2G2019S), 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-LRRK2G2019S, NM-LRRK2G2019S, and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2G2019S and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2G2019S.
Results: Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2G2019S and NM-LRRK2G2019S 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-LRRK2G2019 and rescued the loss of visual function in LRRK2G2019S flies.
Conclusion: There is clear preclinical impairment of mitochondrial function in NM-LRRK2G2019S that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2G2019S and M-LRRK2G2019S as well as on the function of dopaminergic neurons expressing LRRK2G2019S suggests that UDCA is a promising drug for future neuroprotective trials.
GLOSSARY
- ANOVA=
- analysis of variance;
- ATP=
- adenosine 5′-triphosphate;
- CRF=
- contrast response function;
- EOPD=
- early-onset Parkinson disease;
- FDA=
- Food and Drug Administration;
- M-LRRK2G2019S=
- manifesting LRRK2G2019S carriers;
- NM-LRRK2G2019S=
- nonmanifesting LRRK2G2019S carriers;
- PD=
- Parkinson disease;
- SSVEP=
- steady-state visual evoked potentials;
- TUDCA=
- taurine conjugate;
- UDCA=
- ursodeoxycholic acid
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally as joint first authors.
↵‡ These authors contributed equally as joint last authors.
Supplemental data at Neurology.org
Editorial, page 838
- Received March 13, 2014.
- Accepted in final form March 9, 2015.
- © 2015 American Academy of Neurology
AAN Members: Sign in with your AAN member credentials (e-mail or 6-digit Member ID number)
Non-AAN Member subscribers: Sign in with subscriber credentials
Log in using your username and password
Purchase access
Disputes & Debates: Rapid online correspondence
NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
- Stay timely. Submit only on articles published within the last 8 weeks.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- 200 words maximum.
- 5 references maximum. Reference 1 must be the article on which you are commenting.
- 5 authors maximum. Exception: replies can include all original authors of the article.
- Submitted comments are subject to editing and editor review prior to posting.