Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease.
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.
1] Ludwig Institute for Cancer Research, Stockholm, Sweden. [2] Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. [3] Neurodegenerative Diseases Group, Vall d'Hebron Research Institute-CIBERNED, Barcelona, Spain.
Ariadna
A
Laguna
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Nicoletta
N
Schintu
Ludwig Institute for Cancer Research, Stockholm, Sweden.
André
A
Nobre
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Alexandra
A
Alvarsson
Ludwig Institute for Cancer Research, Stockholm, Sweden.
Nikolaos
N
Volakakis
Ludwig Institute for Cancer Research, Stockholm, Sweden.
Jesper Kjaer
JK
Jacobsen
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Marta
M
Gómez-Galán
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Elena
E
Sopova
Ludwig Institute for Cancer Research, Stockholm, Sweden.
Eliza
E
Joodmardi
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Takashi
T
Yoshitake
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Qiaolin
Q
Deng
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Jan
J
Kehr
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Johan
J
Ericson
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Per
P
Svenningsson
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Oleg
O
Shupliakov
1] Ludwig Institute for Cancer Research, Stockholm, Sweden. [2] Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Thomas
T
Perlmann
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D001522:Behavior, Animal; D015306:Biogenic Monoamines / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000502:physiology; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D015306:Biogenic Monoamines; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D004298:Dopamine