Jimenez-Moreno, Natalia and Kollareddy, Madhu and Stathakos, Petros and Moss, Joanna J. and Anton, Zurine and Shoemark, Deborah K. and Sessions, Richard B. and Witzgall, Ralph and Caldwell, Maeve and Lane, Jon D. (2023) ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience. JOURNAL OF CELL BIOLOGY, 222 (5): e201910133. ISSN 0021-9525, 1540-8140
Full text not available from this repository. (Request a copy)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 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. Jimenez-Moreno et al. demonstrate that human ATG8 proteins stimulate transcriptional cell stress protection via binding to the LMX1B transcription factor, an essential determinant of dopaminergic neuronal development and maintenance in the adult brain.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALPHA-SYNUCLEIN; LIR MOTIF; RENAL-DISEASE; AUTOPHAGY; LMX1B; EXPRESSION; PROTEIN; IDENTIFICATION; MAINTENANCE; GENERATION; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Mar 2024 11:33 |
| Last Modified: | 14 Mar 2024 11:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60088 |
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