期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 30, 页码 E4387-E4396出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1520387113
关键词
transcription factors; Parkinson's disease; mitochondrial dysfunctions; protein aggregates; dopamine neurons
资金
- Canadian Institutes of Health Research [MOP 311120, MOP106556]
- Natural Sciences and Engineering Research Council of Canada Grant [418391-2012]
- Fonds du Quebec en Recherche, Sante (FRQS)
- Fonds Quebecois de Recherche sur le Parkinson
- Parkinson Society Canada
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 alpha-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, alpha-synuclein aggregation, and the survival of dopaminergic neurons.
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