Evidence map›Paper›PMID 37384414›Full record

ArticleHuman molecular genetics2023

Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.

Matthew G Williamson, Marta Madureira, William McGuinness, Rachel Heon-Roberts, Elliot D Mock, Kalina Naidoo, Kaitlyn M L Cramb, Maria-Claudia Caiazza, Ana B Malpartida, Martha Lavelle and 7 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.

0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed
10.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

42 citing papers in PubMed, 50 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 3 institutions in 3 countries.

Matthew G WilliamsonOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Marta MadureiraOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.ORCID 0000-0003-3076-4223
William McGuinnessOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Rachel Heon-RobertsOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Elliot D MockOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Kalina NaidooOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Kaitlyn M L CrambOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Maria-Claudia CaiazzaOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.ORCID 0000-0002-0568-964X
Ana B MalpartidaOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Martha LavelleOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Katrina SavoryOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Stewart W HumbleOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Ryan PattersonOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
John B DavisOxford Drug Discovery Institute, Centre of Medicines Discovery, University of Oxford, NDM Research Building, Old Road Campus, Oxford OX3 7FZ, UK.
Natalie Connor-RobsonOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Brent J RyanOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
Richard Wade-MartinsOxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
University of Oxford · GBNational Institutes of Health · USUniversidade do Porto · PT

Funding

Medical Research Council MC_EX_MR/N50192X/1Medical Research Council MR/N029453/1Wellcome Trust 223202/Z/21/Z
6 · The paper itself

Abstract

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson's disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation.

Indexed as

Induced Pluripotent Stem CellsParkinson DiseaseAgedAnimalsHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MitochondriaMitophagyMutationRatsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, human

Identifiers

PMID37384414
PMCPMC10481106
OpenAlexW4382536336

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.