Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease

Nat Neurosci. 2015 Jun;18(6):826-35. doi: 10.1038/nn.4004. Epub 2015 Apr 27.


The role of developmental transcription factors in maintenance of neuronal properties and in disease remains poorly understood. Lmx1a and Lmx1b are key transcription factors required for the early specification of ventral midbrain dopamine (mDA) neurons. Here we show that conditional ablation of Lmx1a and Lmx1b after mDA neuron specification resulted in abnormalities that show striking resemblance to early cellular abnormalities seen in Parkinson's disease. We found that Lmx1b was required for the normal execution of the autophagic-lysosomal pathway and for the integrity of dopaminergic nerve terminals and long-term mDA neuronal survival. Notably, human LMX1B expression was decreased in mDA neurons in brain tissue affected by Parkinson's disease. Thus, these results reveal a sustained and essential requirement of Lmx1b for the function of midbrain mDA neurons and suggest that its dysfunction is associated with Parkinson's disease pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Behavior, Animal
  • Biogenic Monoamines / metabolism
  • Cell Survival / drug effects
  • Dopamine / metabolism*
  • Dopaminergic Neurons / physiology
  • Humans
  • LIM-Homeodomain Proteins / genetics
  • LIM-Homeodomain Proteins / metabolism*
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • Parkinson Disease / genetics
  • Parkinson Disease / physiopathology*
  • Parkinson Disease / psychology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology


  • Biogenic Monoamines
  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Transcription Factors
  • Dopamine