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Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4387-96. doi: 10.1073/pnas.1520387113. Epub 2016 Jul 12.

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.

Author information

1
Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;
2
Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;
3
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;
4
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;
5
The Francis Crick Institute, London, NW1 2BE, United Kingdom;
6
Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de recherche du Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.
7
Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada; martin.levesque@fmed.ulaval.ca.

Abstract

The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein(+) inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons.

KEYWORDS:

Parkinson's disease; dopamine neurons; mitochondrial dysfunctions; protein aggregates; transcription factors

PMID:
27407143
PMCID:
PMC4968767
DOI:
10.1073/pnas.1520387113
[Indexed for MEDLINE]
Free PMC Article

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