Neuroscience Letters 531 (2012) 182–187 Contents lists available at SciVerse ScienceDirect Neuroscience Letters j our nal ho me p ag e: www.elsevier.com/locate/neulet Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion Alfredo Giménez-Cassina a,b,∗∗ , Filip Lim a,b , Javier Díaz-Nido a,b,∗ a Dept. de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC) Universidad Autónoma de Madrid, 28049 Madrid, Spain b U-748, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain h i g h l i g h t s ◮ GSK-3 inhibition increases BDNF secretion. ◮ BDNF signalling protects neuronal cells from rotenone-induced cell death. ◮ BDNF drives subcellular redistribution of hexokinase II. ◮ Mitochondrial hexokinase II mediates BDNF-conferred neuroprotection. a r t i c l e i n f o Article history: Received 20 August 2012 Received in revised form 23 September 2012 Accepted 9 October 2012 Keywords: GSK-3 BDNF Hexokinase II Neuroprotection a b s t r a c t Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. Likewise, activation of glycogen synthase kinase-3 (GSK-3) has been proposed to play an important role in neu- rodegeneration. This multifunctional protein kinase is involved in a number of cellular functions and we previously showed that chronic inhibition of GSK-3 protects neuronal cells against mitochondrial dysfunction-elicited cell death, through a mechanism involving increased glucose metabolism and the translocation of hexokinase II (HKII) to mitochondria. Here, we sought to gain deeper insight into the molecular basis of this neuroprotection. We found that chronic inhibition of GSK-3, either genetically or pharmacologically, elicited a marked increase in brain-derived neurotrophic factor (BDNF) secretion, which in turn conferred resistance to mitochondrial dysfunction through subcellular re-distribution of HKII. These results define a molecular pathway through which chronic inhibition of GSK-3 may protect neuronal cells from death. Moreover, they highlight the potential benefits of enhanced neurotrophic factor secretion as a therapeutic approach to treat neurodegenerative diseases. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Glycogen synthase kinase-3 (GSK-3) is a Ser/Thr protein kinase involved in a wide range of cellular processes, including metabolism, transcription, cytoskeleton dynamics and apoptosis [10]. In recent years, evidence has emerged that GSK-3 plays a prominent role in neurodegenerative disorders, and its inhibition has been shown to protect neuronal cells against an array of ∗ Corresponding author at: Centro de Biología Molecular “Severo Ochoa”, Univer- sidad Autónoma de Madrid, 28049 Madrid, Spain. Tel.: +34 91 196 4562. ∗∗ Corresponding author. Present address: Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. Tel.: +1 617 632 6412. E-mail addresses: Alfredo gimenez-cassina@dfci.harvard.edu (A. Giménez-Cassina), javier.diaznido@uam.es (J. Díaz-Nido). apoptotic insults that mimic selective neurodegenerative diseases. Thus, GSK-3 has been proposed as a promising therapeutic target for the treatment of neurodegenerative disorders [3,10,15]. Recent studies have uncovered some of the cell death pathways in which GSK-3 is directly implicated [15]. However, in certain cases pre-inhibition of GSK-3 is required prior to exposure to the apoptotic stimulus to confer maximal resistance to some such stimuli [8,19]. In particular, chronic inhibition of GSK-3 protects neuronal cells from mitochondrial dysfunction-induced cell death, a common feature to most neurodegenerative diseases [8,16]. The need for pre-inhibition of GSK-3 to elicit neuroprotection suggests underlying changes in the expression, localization and activation of different proteins. Remarkably, GSK-3 has a broad range of sub- strates, including a number of transcription factors whose activity can be modulated by phosphorylation [10,15]. In the present study we sought to identify some of the molec- ular mechanisms underlying neuroprotection following chronic 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2012.10.046