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
|Journal||The Journal of cell biology|
|Publication status||Submitted - 2020|
- LMX1A; LMX1B; autophagy; dopaminergic neuron; mDAN; Parkinson’s disease; iPSC; transcription; cofactor; LIR motif.
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Sadaf R Alam (Manager), Steven A Chapman (Manager), Polly E Eccleston (Other), Simon H Atack (Other) & D A G Williams (Manager)