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Creatine (Cr) is a nitrogenous organic acid and plays roles such as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes arginine:glycine amidinotransferase and guanidinoacetate methyltransferase, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause creatine deficiency syndromes (CDS). CDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. Among CDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies, and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models, and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8^(Y389C) knock-in rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency, and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunctions, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain., Journal of Inherited Metabolic Disease, 45 (2), ISSN:1573-2665, ISSN:0141-8955

Creatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CCDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.

Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in theSlc6a8gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features.Slc6a8xY389CKI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

In the Acknowledgments of our report we unintentionally omitted to include a sentence stating that J.G. holds a postdoctoral fellowship (JAE-Doc) from the Program “Junta para la Ampliacion de Estudios” co-funded by the Fondo Social Europeo (FSE). The authors regret this omission.

Criado-García, Olga et al., Lafora disease (LD), a fatal neurodegenerative disorder characterized by the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of the intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. We have generated a malin-deficient (Epm2b-/-) mouse with a phenotype similar to that of LD patients. By 3-6 months of age, Epm2b-/- mice present neurological and behavioral abnormalities that correlate with a massive presence of LBs in the cortex, hippocampus and cerebellum. Sixteen-day-old Epm2b-/- mice, without detectable LBs, show an impairment of macroautophagy (hereafter called autophagy), which remains compromised in adult animals. These data demonstrate similarities between the Epm2a-/- and Epm2b-/- mice that provide further insights into LD pathogenesis. They illustrate that the dysfunction of autophagy is a consequence of the lack of laforin-malin complexes and a common feature of both mouse models of LD. Because this dysfunction precedes other pathological manifestations, we propose that decreased autophagy plays a primary role in the formation of LBs and it is critical in LD pathogenesis. © The Author 2011. Published by Oxford University Press. All rights reserved., This work was funded by the Spanish Ministerio de Ciencia eInnovacio ́ n (SAF2008-00226 to S.R.C.; BFU2007-61774 andBFU2010-16031toP.B.;BFU2008-00186toE.K.;SAF2008-01907 to P.S.; and SAF2010-18586 to J.M.S.), theRed de Biobancos del FIS (RD09/0076/00011 to C.N.), theFondo de Investigacio ́ n Sanitaria (PI10/02628 to C.N.;PI070023 to M.S.), the Fundacio ́ n Marato TV3 (Ref. 100130to P.S., E.K. and S.R.C.) and the Centro de Investigacio ́ n Bio-me ́dica en Red de Enfermedades Raras (CIBERER).A.M.G.-C. holds a fellowship from the Fundacio ́ n ConchitaRa ́bago

Knecht, Erwin et al., Lafora disease (LD), a fatal neurodegenerative disorder characterized by intracellular inclusions called Lafora bodies (LBs), is caused by recessive loss-of-function mutations in the genes encoding either laforin or malin. Previous studies suggested a role of these proteins in regulating glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. Here we review our recent finding that dysfunction of autophagy is a common feature of both laforin- and malin-deficient mice, preceding other pathological manifestations. We propose that autophagy plays a primary role in LD pathogenesis and is a potential target for its treatment. © 2012 Landes Bioscience., Spanish Ministry of Science and Innovation (SAF2008-00226 to SRdeC, BFU2010-16031 to PB; BFU2008-00186, SAF2008-01907, SAF2010-18586); the Red de Biobancos del FIS (RD09/0076/00011); the Fondo de Investigación Sanitaria (PI10/02628, PI070023); the Fundación Marato TV3 (Ref.100130); the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Fundación Conchita Rábago

Long-term changes of synaptic plasticity depend on protein synthesis and transcription. Ng (neurogranin) is a small protein concentrated at dendrites and spines of forebrain neurons, involved in synaptic plasticity through the regulation of CaM (calmodulin)-mediated signalling. Ng presents a central IQ motif that mediates its binding to CaM and PA (phosphatidic acid) and that can be phosphorylated by PKC (protein kinase C). In the present manuscript, we report that Ng displays a strong nuclear localization when expressed in cell lines and hippocampal neurons, either alone or fused to GFP (green fluorescent protein; GFP–Ng). Furthermore, using subcellular fractionation and immunocytochemical techniques, we were able to localize endogenous Ng in the nuclei of rat forebrain neurons. Nuclear localization of Ng depends on its IQ motif and is reduced by binding to cytoplasmic CaM. Also, PKC stimulation induces a transient nuclear translocation of Ng in acute hippocampal slices. A similar translocation is observed in the neurons of the cerebral cortex and hippocampus after the induction of generalized seizures in adult rats. In summary, the results of the present study show that a fraction of rat brain Ng is localized in the neuronal nuclei and that synaptic activity regulates its translocation from the cytoplasm. The possible involvement of Ng in the regulation of intranuclear Ca2+/CaM-dependent signalling and gene expression is discussed.