TY  - JOUR
AU  - Tutas, Janine
AU  - Tolve, Marianna
AU  - Özer-Yildiz, Ebru
AU  - Ickert, Lotte
AU  - Klein, Ines
AU  - Silverman, Quinn
AU  - Liebsch, Filip
AU  - Dethloff, Frederik
AU  - Giavalisco, Patrick
AU  - Endepols, Heike
AU  - Georgomanolis, Theodoros
AU  - Neumaier, Bernd
AU  - Drzezga, Alexander
AU  - Schwarz, Guenter
AU  - Thorens, Bernard
AU  - Gatto, Graziana
AU  - Frezza, Christian
AU  - Kononenko, Natalia L
TI  - Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
JO  - Nature metabolism
VL  - 7
IS  - 2
SN  - 2522-5812
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00376
SP  - 297 - 320
PY  - 2025
AB  - Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
KW  - Animals
KW  - Autophagy-Related Protein 5: metabolism
KW  - Autophagy-Related Protein 5: genetics
KW  - Mice
KW  - Glycolysis
KW  - Autophagy
KW  - Cerebellum: metabolism
KW  - Purkinje Cells: metabolism
KW  - Glucose: metabolism
KW  - Glucose Transporter Type 2: metabolism
KW  - Mice, Knockout
KW  - Autophagy-Related Protein 5 (NLM Chemicals)
KW  - Atg5 protein, mouse (NLM Chemicals)
KW  - Glucose (NLM Chemicals)
KW  - Glucose Transporter Type 2 (NLM Chemicals)
KW  - Slc2a2 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39815080
DO  - DOI:10.1038/s42255-024-01196-4
UR  - https://pub.dzne.de/record/277313
ER  -