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LIR-dependent LMX1A/LMX1B autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience

biorxiv. 2019; 
Natalia Jiménez-Moreno,  Petros Stathakos,  Zuriñe Antón,  Deborah K. Shoemark,  Richard B. Sessions,  Ralph Witzgall,  Maeve Caldwell,   View Jon D. Lane
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摘要

The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors in iPSC-derived human mDANs, each contributing to the expression of important autophagy genes including ULK1, ATG7, ATG16L1 and TFEB. Suppression of LMX1A and LMX1B in mDANs reduces basal autophagy, lowers mitochondrial respiration, and elevates mitochondrial ROS levels; meanwhile overexpression protects against rotenone poisoning in mDANs in vitro. Significantly, we show that LMX1A and LMX1B bind to multiple ATG8 proteins via LIR-type interactions, in a manner dependent on subcellular locali... More

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