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UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 G2019S carriers and in vivo
Open accessAbstract
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.
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“In addition, ursodeoxycholic acid (UDCA) has a protective effect on the function of mitochondria and dopaminergic neurons in a Parkinson's disease model.219”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [219]
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References 27 · Cited by 131
Metadata
- Authors
- Mortiboys, H., Furmston, R., Bronstad, G., Aasly, J., Elliott, C., & Bandmann, O.
- Affiliations
- St Olav's University Hospital (NO)
- 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.
- Venue
- Neurology
- Published
- 2015-09-08
- Volume
- 85
- Issue
- 10
- Pages
- 846-852
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC4560055
- OpenAlex
- W2106045149
- Semantic Scholar
- ad18335a8bdfe8bd413189b46c93e8b1f649501e
- Cited by
- 131
- References
- 27
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 9 · 2023: 11 · 2022: 9 · 2021: 16 · 2020: 18 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 8 · 2015: 5
- FWCI
- 8.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (097829)
- Parkinson's UK (G‐1202, H1201, G-1007)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- ursodeoxycholic acid, LRRK2 G2019S mutation, Parkinson's disease, mitochondrial dysfunction, ATP levels, mitochondrial morphology, dopaminergic neurons, neuroprotection, visual function
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Adult, Aged, Animals, Drosophila, Female, Heterozygote, Humans, Male, Middle Aged, Mitochondria, Parkinson Disease, Ursodeoxycholic Acid, Treatment Outcome, Protein Serine-Threonine Kinases, Animals, Genetically Modified
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