Article

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

  • Nature Neuroscience volume 18, pages 826835 (2015)
  • doi:10.1038/nn.4004
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Abstract

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.

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Acknowledgements

We thank T. Samuelsson, H. Lunden-Miguel and C.-Y. Leung for technical assistance, and members of the Ericson and Perlmann laboratories for discussions. We thank S.-L. Ang (National Institute for Medical Research, London), N.-G. Larsson (Max Planck Institute, Köln) and G. Schütz (DKFZ, Heidelberg) for providing mouse lines. We thank T. Beach at the Banner Sun Health Research Institute, Arizona, USA for providing postmortem human brain samples. This work was supported by funding from the European Union, Seventh Framework Programme under grant agreement mdDANeurodev, NeuroStemCell and Synsys (T.P., J.E. and O.S.), from the Swedish Strategic Research Foundation (SSF; T.P. and P.S.), from the Swedish Research Council, and from Hjärnfonden and Parkinsonfonden (O.S.). The human tissue donation program was supported by the US National Institutes of Health (U24 NS072026 and P30 AG19610), the Arizona Department of Health Services, the Arizona Biomedical Research Commission and the Michael J. Fox Foundation for Parkinson's Research. A.L. was supported by a Marie Curie Intra-European Fellowship for Career Development.

Author information

Author notes

    • Nicoletta Schintu
    •  & André Nobre

    These authors contributed equally to this work.

Affiliations

  1. Ludwig Institute for Cancer Research, Stockholm, Sweden.

    • Ariadna Laguna
    • , André Nobre
    • , Nikolaos Volakakis
    • , Jesper Kjaer Jacobsen
    • , Eliza Joodmardi
    •  & Thomas Perlmann
  2. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

    • Ariadna Laguna
    • , Qiaolin Deng
    • , Johan Ericson
    •  & Thomas Perlmann
  3. Neurodegenerative Diseases Group, Vall d'Hebron Research Institute-CIBERNED, Barcelona, Spain.

    • Ariadna Laguna
  4. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Nicoletta Schintu
    • , Alexandra Alvarsson
    •  & Per Svenningsson
  5. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

    • Marta Gómez-Galán
    • , Elena Sopova
    •  & Oleg Shupliakov
  6. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

    • Takashi Yoshitake
    •  & Jan Kehr

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Contributions

A.L. planned all experiments, performed histological, gene expression and western blot analyses and wrote the manuscript; N.S. performed behavioral analysis and dissection of mouse brain tissue; A.N. performed primary ventral midbrain cultures and gene expression analysis; A.A. performed behavioral analysis; N.V. cloned and produced lentiviruses; J.K.J. performed stereological and western blot analyses; M.G.G. performed electrophysiological analysis; E.S. performed electron microscopy analysis; E.J. performed histological analysis; T.Y. and J.K. performed high-performance liquid chromatography; Q.D. and J.E. generated conditional Lmx1a gene targeted mice and helped with planning; P.S. helped with analysis and planning; O.S. performed electron microscopy analysis, helped with analysis and with writing the manuscript; T.P. together with A.L. planned all experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ariadna Laguna or Thomas Perlmann.

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