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.
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
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.
发育转录因子在维持神经元特性和疾病中的作用仍知之甚少。Lmx1a 和 Lmx1b 是早期中脑腹侧多巴胺 (mDA) 神经元特化所必需的关键转录因子。在这里，我们发现 mDA 神经元特化后 Lmx1a 和 Lmx1b 的条件性缺失导致了与帕金森病中早期细胞异常惊人相似的异常。我们发现 Lmx1b 对于自噬溶酶体途径的正常执行以及多巴胺能神经末梢的完整性和长期 mDA 神经元存活是必需的。值得注意的是，在帕金森病受累脑组织的 mDA 神经元中，人类 LMX1B 的表达减少。因此，这些结果揭示了 Lmx1b 对中脑 mDA 神经元功能的持续和必需的要求，并表明其功能障碍与帕金森病的发病机制有关。
