ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience

Natalia Jimenez Moreno, Madhu Kollareddy, Petros Stathakos, Joanna J Moss, Zuri Anton, Deborah K Shoemark, Richard B Sessions, Ralph Witzgall, Maeve Caldwell, Jon D Lane*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)

Abstract

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 that provide cellular stress protection. Their suppression dampens the autophagy response, lowers mitochondrial respiration, and elevates mitochondrial ROS, and their inducible overexpression protects against rotenone toxicity in human iPSC-derived mDANs in vitro. Significantly, we show that LMX1A and LMX1B stability is in part regulated by autophagy, and that these transcription factors bind to multiple ATG8 proteins. Binding is dependent on subcellular localisation and nutrient status, with LMX1B interacting with LC3B in the nucleus under basal conditions and associating with both cytosolic and nuclear LC3B during nutrient starvation. Crucially, ATG8 binding stimulates LMX1B-mediated transcription for efficient autophagy and cell stress protection, thereby establishing a novel LMX1B-autophagy regulatory axis that contributes to mDAN maintenance and survival in the adult brain.
Original languageEnglish
JournalJournal of Cell Biology
Volume222
Issue number5
DOIs
Publication statusPublished - 4 Apr 2023

Bibliographical note

Publisher Copyright:
© 2023 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.

Keywords

  • LMX1A; LMX1B; autophagy; dopaminergic neuron; mDAN; Parkinson’s disease; iPSC; transcription; cofactor; LIR motif.

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