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

doi:10.1083/jcb.201910133

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 journal › Article (Academic Journal) › peer-review

9 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 language	English
Journal	Journal of Cell Biology
Volume	222
Issue number	5
DOIs	https://doi.org/10.1083/jcb.201910133
Publication status	Published - 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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title = "ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience",

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.",

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author = "{Jimenez Moreno}, Natalia and Madhu Kollareddy and Petros Stathakos and Moss, {Joanna J} and Zuri Anton and Shoemark, {Deborah K} and Sessions, {Richard B} and Ralph Witzgall and Maeve Caldwell and Lane, {Jon D}",

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doi = "10.1083/jcb.201910133",

language = "English",

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T1 - ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience

AU - Jimenez Moreno, Natalia

AU - Kollareddy, Madhu

AU - Stathakos, Petros

AU - Moss, Joanna J

AU - Anton, Zuri

AU - Shoemark, Deborah K

AU - Sessions, Richard B

AU - Witzgall, Ralph

AU - Caldwell, Maeve

AU - Lane, Jon D

N1 - 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.

PY - 2023/4/4

Y1 - 2023/4/4

N2 - 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.

AB - 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.

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

U2 - 10.1083/jcb.201910133

DO - 10.1083/jcb.201910133

M3 - Article (Academic Journal)

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VL - 222

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 5

ER -

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

Abstract

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