Nat Metab co-auth.: B.Thorens

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Janine Tutas 1 2Marianna Tolve 1 2Ebru Özer-Yildiz 1 2Lotte Ickert 1 2Ines Klein 3Quinn Silverman 3Filip Liebsch 4Frederik Dethloff 5Patrick Giavalisco 5Heike Endepols 6 7 8Theodoros Georgomanolis 1Bernd Neumaier 7 8Alexander Drzezga 7 9 10Guenter Schwarz 4 11Bernard Thorens 12Graziana Gatto 3Christian Frezza 1 13Natalia L Kononenko 14 15 16 17

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Abstract

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.