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

Natalia Jimenez Moreno, Petros Stathakos, Zuri Anton, Deborah K Shoemark, Richard B Sessions, Ralph Witzgall, Maeve A Caldwell, Jon D Lane

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

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 in iPSC-derived human mDANs. Their suppression
reduces basal autophagy, lowers mitochondrial respiration, and elevates mitochondrial ROS
levels; while their inducuble overexpression protects against rotenone toxicity 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 localisation and nutrient status: LMX1B
interacts with LC3B in the nucleus under basal conditions via a C-terminal LIR, but binds to
cytosolic LC3B and is degraded by autophagy during nutrient starvation. Crucially, ATG8 binding
stimulates LMX1B-mediated transcription, whereas LIR mutant LMX1B is unable to protect mDANs
against rotenone. This establishes a novel LMX1B-autophagy regulatory axis that contributes to
mDAN maintenance in the adult midbrain with implications for our understanding of mDAN decline
in PD.
Original languageEnglish
JournalThe Journal of cell biology
Publication statusSubmitted - 2020

Keywords

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

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