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Glycogen: a Trojan Horse for Neurons NEWS AND VIEWS Glycogen: a Trojan horse for neurons Pierre J Magistretti & Igor Allaman Neural activity leads to the mobilization of energy from glycogen in astrocytes. A new paper reports that neurons have an ambivalent relationship with glycogen: they can synthesize it themselves, but that synthesis induces apoptosis. Presumably for this reason, neurons normally inhibit glycogen synthesis through two redundant pathways. Glycogen, the single largest energy reserve of the brain1, is mobilized by neuronal activity2, probably to match the increased a b energy requirements associated with it. NA,VIP, ADE, ATP Glycogen metabolism provides a clear Astrocyte http://www.nature.com/natureneuroscience example of neuron-glia metabolic coupling. Glycogen GS P ‘Glycogen’ P P Malin Glycogen is almost exclusively localized in P GS P PTG LiCl PP Laforin astrocytes, whereas the neurotransmitters P Lactate P P P Malin P GS P Laforin and neuromodulators that mobilize glycogen PPP are released by active neurons3. Neuron Glycogen is regulated by two key enzymes, glycogen synthase and glycogen phosphorylase. Phosphorylation inhibits glycogen synthase and Ris-Vicari Katie increases the activity of glycogen phosphorylase, resulting in glycogenolysis. In cortical slices, Figure 1 Glycogen metabolism in the brain and its dysregulation in Lafora disease. (a) Under normal glycogenolysis is triggered by noradrenaline, circumstances, astrocytes synthesize and store glycogen. Neurotransmitters such as noradrenaline Nature Publishing Group Group Nature Publishing (NA), vasoactive intestinal peptide (VIP), adenosine (ADE) or ATP trigger the breakdown of glycogen 7 vasoactive intestinal peptide, adenosine to enable the release of lactate, which is taken up as fuel by neurons. In neurons, glycogen 1 200 and ATP through cyclic AMP– or calcium- synthase (GS) is hyperphosphorylated and thereby inactivated. The malin-laforin complex targets © dependent intracellular signaling. During hyperphosphorylated GS for ubiquitin proteasome–dependent degradation. No glycogen is synthesized glycogenolysis, astrocytes release lactate as an in neurons. (b) In Lafora disease, either malin or laforin is mutated. Thus, hyperphosphorylated GS energy substrate for neurons4–6. This is a nice escapes degradation and can be activated by dephosphorylation. Vilchez et al.7 show that either story, to which Vilchez et al.7 add an unexpected inhibition of glycogen synthase kinase by LiCl or by overexpression of the protein phosphatase 1 and very instructive chapter in this issue. regulatory subunit PTG can activate GS in neurons, leading to the accumulation of abnormally branched glycogen species that are toxic to neurons (as indicated by the dashed cell outline.) The authors provide evidence that neurons also have the enzymatic machinery for synthesizing glycogen, as they express glycogen synthase, but that its activity is kept silent neurons by triggering apoptotic signaling. In authors show that overexpression of protein by a series of well-coordinated intracellular addition, the glycogen that neurons synthesize targeting to glycogen (PTG), a regulatory mechanisms. They go on to show that failure is abnormal and causes the accumulation subunit of protein phosphatase 1 that to keep glycogen synthase under control, of granular deposits that cannot be mobilized. activates glycogen synthase by stimulating its resulting in glycogen synthesis, damages Such deposits, dubbed Lafora bodies, are dephosphorylation8,9, also leads to abnormal characteristic of a form of progressive glycogen accumulation in neurons (Fig. 1). myoclonus epilepsy, Lafora disease. The study7 also provides a molecular link The authors are in the Laboratory of Vilchez et al.7 also unravel the mechanisms between neuronal accumulation of abnormal Neuroenergetics and Cellular Dynamics, Brain that go astray when neurons synthesize glycogen deposits and Lafora disease. This Mind Institute, Ecole Polytechnique Fédérale glycogen. First the authors show that autosomal recessive form of epilepsy— de Lausanne, AAB 1 33 (Bâtiment AAB), glycogen synthase is present in cultured characterized by tonic-clonic, myoclonus and Station 15, Lausanne, Switzerland CH-1015. neurons in a highly phosphorylated, and absence seizures progressing to dementia, Pierre Magistretti is also in the Centre de thus inactive, state. When dephosphorylation vegetative state and death within a decade of Neurosciences Psychiatriques, Centre Hospitalier is induced by LiCl, an inhibitor of glycogen its inception during adolescence—is associated Universitaire Vaudois, Département de Psychiatrie, synthase kinase (the main kinase that keeps with mutations in two genes encoding the Lausanne, Switzerland. glycogen synthase phosphorylated), neurons enzymes laforin and malin. Patients with e-mail: [email protected] synthesize large amounts of glycogen. The mutations of either laforin or malin express NATURE NEUROSCIENCE VOLUME 10 | NUMBER 11 | NOVEMBER 2007 1341 NEWS AND VIEWS similar clinical manifestations, suggesting that program. Accordingly, neurons have effective glycogen synthesis, but then activate complex these two proteins operate through common and redundant mechanisms for inhibiting protein-protein interaction mechanisms to mechanisms10. Laforin is a phosphatase that glycogen synthesis. The first mechanism is to keep this potential inhibited? Paradoxically, interacts with PTG11 and has a functional keep glycogen synthase in a phosphorylated this inhibitory mechanism is likely to carbohydrate-binding domain. Malin is a (inactive) state. The second is to degrade PTG consume energy. One possibility raised by the ubiquitin ligase that causes ubiquitination and and glycogen synthase in a tonic, proteasome- authors is that glycogen synthase has other, proteasome-mediated degradation of laforin12. dependent manner involving the malin-laforin yet undiscovered, roles in neuronal functions. In a series of elegant experiments, complex. Mutations in the genes encoding This article is likely to bring a renewed Vilchez et al.7 brought the pieces of the puzzle these enzymes are found in individuals attention to the study of glycogen regulation together. They showed that the massive affected by Lafora disease, a condition that in the brain, a field that has evolved in a induction of glycogen synthase activity and is histopathologically characterized by low-key but steady fashion over the last of abnormal glycogen deposition induced the presence of glycogen-like deposits in 25 years and is likely to still bring surprising in neurons when PTG is overexpressed is neurons. Thus it appears that neurons have insights into neuron-glia physiology and abolished by the concomitant overexpression an ambivalent relationship with glycogen; pathology in the years to come3. of both laforin and malin. (Overexpressing they benefit from it as long as it is localized 1. Magistretti, P.J. Brain energy metabolism. in either one alone had no effect.) They also in astrocytes and so long as they are provided Fundamental Neuroscience (eds. Squire, L.R. et al.) demonstrated that the malin-laforin complex with energy substrates deriving from it, most 339–360 (Academic Press, San Diego, 2003). 2. Swanson, R.A., Morton, M.M., Sagar, S.M. & markedly decreases PTG and glycogen synthase likely lactate. Increasing astrocytic glycogen Sharp, F.R. Neuroscience 51, 451–461 (1992). protein levels, thus inactivating the glycogen- has a neuroprotective effect in experimental 3. Magistretti, P.J. J. Exp. Biol. 209, 2304–2311 (2006). synthesizing machinery, through a mechanism stroke5,14. However, when synthesized inside 4. Dringen, R., Gebhardt, R. & Hamprecht, B. Brain Res. 623, 208–214 (1993). mediated by activation of the ubiquitin- of neurons, glycogen acts as a Trojan horse, 5. Brown, A.M., Tekkok, S.B. & Ransom, B.R. proteasome pathway. If a form of malin triggering mechanisms that lead to neuronal Neurochem. Int. 45, 529–536 (2004). containing a mutation observed in individuals dysfunction and eventually death. 6. Poitry-Yamate, C.L., Poitry, S. & Tsacopoulos, M. J. Neurosci. 15, 5179–5191 (1995). http://www.nature.com/natureneuroscience 7 with Lafora disease is cotransfected in neurons Although Vilchez et al. bring some new 7. Vilchez, D. et al. Nat. Neurosci. 10, 1407–1413 with laforin instead of the wild-type malin, the insights to the regulation of brain glycogen (2007). 8. Newgard, C.B., Brady, M.J., O’Doherty, R.M. & inhibitory effect on PTG and glycogen synthase metabolism, this report raises several questions. Saltiel, A.R. Diabetes 49, 1967–1977 (2000). expression and activity is lost. For example, through what mechanism(s) 9. Allaman, I., Pellerin, L. & Magistretti, P.J. Glia 30, These results provide an explanation for does accumulation of abnormally branched 382–391 (2000). 10. Ganesh, S., Puri, R., Singh, S., Mittal, S. & Dubey, D. previous puzzling observations of glycogen glycogen trigger apoptosis? Why are astrocytes J. Hum. Genet. 51, 1–8 (2006). synthase in neurons in situ13, although ‘immune’ to the destructive effects of glycogen 11. Fernandez-Sanchez, M.E. et al. Hum. Mol. Genet. 12, 3161–3171 (2003). glycogen could not be observed in these accumulation? The actual link between 12. Gentry, M.S., Worby, C.A. & Dixon, J.E. Proc. Natl. 7 cells in the adult brain. Vilchez et al. report glycogen accumulation in neurons and the Acad. Sci. USA 102, 8501–8506 (2005). that neurons have the capacity to synthesize clinical phenotype of Lafora disease still 13. Inoue, N., Matsukado,
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