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

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 autoph...

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Autores principales: Jiménez-Moreno, Natalia, Kollareddy, Madhu, Stathakos, Petros, Moss, Joanna J., Antón, Zuriñe, Shoemark, Deborah K., Sessions, Richard B., Witzgall, Ralph, Caldwell, Maeve, Lane, Jon D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075225/
https://www.ncbi.nlm.nih.gov/pubmed/37014324
http://dx.doi.org/10.1083/jcb.201910133
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author Jiménez-Moreno, Natalia
Kollareddy, Madhu
Stathakos, Petros
Moss, Joanna J.
Antón, Zuriñe
Shoemark, Deborah K.
Sessions, Richard B.
Witzgall, Ralph
Caldwell, Maeve
Lane, Jon D.
author_facet Jiménez-Moreno, Natalia
Kollareddy, Madhu
Stathakos, Petros
Moss, Joanna J.
Antón, Zuriñe
Shoemark, Deborah K.
Sessions, Richard B.
Witzgall, Ralph
Caldwell, Maeve
Lane, Jon D.
author_sort Jiménez-Moreno, Natalia
collection PubMed
description 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.
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spelling pubmed-100752252023-04-06 ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience Jiménez-Moreno, Natalia Kollareddy, Madhu Stathakos, Petros Moss, Joanna J. Antón, Zuriñe Shoemark, Deborah K. Sessions, Richard B. Witzgall, Ralph Caldwell, Maeve Lane, Jon D. J Cell Biol Article 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. Rockefeller University Press 2023-04-04 /pmc/articles/PMC10075225/ /pubmed/37014324 http://dx.doi.org/10.1083/jcb.201910133 Text en © 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. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jiménez-Moreno, Natalia
Kollareddy, Madhu
Stathakos, Petros
Moss, Joanna J.
Antón, Zuriñe
Shoemark, Deborah K.
Sessions, Richard B.
Witzgall, Ralph
Caldwell, Maeve
Lane, Jon D.
ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title_full ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title_fullStr ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title_full_unstemmed ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title_short ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
title_sort atg8-dependent lmx1b-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075225/
https://www.ncbi.nlm.nih.gov/pubmed/37014324
http://dx.doi.org/10.1083/jcb.201910133
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