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

Autor:	Jiménez-Moreno N; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK., Kollareddy M; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK., Stathakos P; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK., Moss JJ; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK., Antón Z; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK., Shoemark DK; School of Biochemistry, University of Bristol , Bristol, UK., Sessions RB; School of Biochemistry, University of Bristol , Bristol, UK., Witzgall R; Institute for Molecular and Cellular Anatomy, University of Regensburg , Regensburg, Germany., Caldwell M; Trinity College Institute for Neuroscience, Trinity College Dublin , Dublin, Ireland., Lane JD; Cell Biology Laboratories, School of Biochemistry, University of Bristol , Bristol, UK.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2023 May 01; Vol. 222 (5). Date of Electronic Publication: 2023 Apr 04.
DOI:	10.1083/jcb.201910133
Abstrakt:	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 localization 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. (© 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.)
Databáze:	MEDLINE
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