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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / genetics
  • DNA Damage
  • Dopaminergic Neurons / metabolism*
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • LIM-Homeodomain Proteins / deficiency
  • LIM-Homeodomain Proteins / genetics*
  • Mesencephalon / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Oxidative Stress
  • Protein Aggregation, Pathological
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • alpha-Synuclein / metabolism


  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Lmx1a protein, mouse
  • Transcription Factors
  • alpha-Synuclein