Cystine accumulation in the CNS results in severe age-related memory decits.pdf

NA t m t r c O C t ? K 1 g d a t D f M f 0 dARTICLE IN PRESSBA-6928; No. of Pages 14 Neurobiology of Aging xxx (2007) xxx–xxx Cystine accumulation in the CNS results in severe age-related memory deficits Tangui Maurice a,b,c, Claire Hippert d,e, Nicolas Serratrice d,e, Gre?gor Dubois d,e, Chantal Jacquet d,e, Corinne Antignac f,g, Eric J. Kremer d,e, Vasiliki Kalatzis d,e,? a Inserm U710, 34095 Montpellier, France b EPHE, 75017 Paris, France c Universite? de Montpellier II, 34095 Montpellier, France d Institut de Ge?ne?tique Mole?culaire de Montpellier, CNRS, 34293 Montpellier, France e Universite?s Montpellier 1 II, 34293 Montpellier, France f Inserm U574, 75015 Paris, France g Universite? Paris Descartes, Faculte? de Me?decine Rene? Descartes, UMRS574, 75015 Paris, France Received 11 April 2007; received in revised form 21 August 2007; accepted 18 September 2007 bstract Cystinosis is a lysosomal storage disorder characterised by progressive cystine accumulation. The causative gene,CTNS, encodes cystinosin, he lysosomal cystine transporter. Neurological deterioration is one of the last symptoms to appear and the least well characterised. Visuospatial emory deficits have been documented in patients. To determine whether the cystinosis mouse model presents similar anomalies, we studied he learning and memory abilities of young and middle-agedCtns?/? mice. We did not detect deficits in youngCtns?/? mice. In contrast, spatial eference and working memory deficits were detected in middle-aged Ctns?/? mice. Elevated cystine levels were detected in the hippocampus, erebellum, forebrain and brainstem of all Ctns?/? mice, which increased with age and were consistent with the appearance of impairments. ur results strongly suggest that the cystinosis-associated CNS anomalies are due to progressive cystine accumulation. Furthermore, the tns?/? mice serve as a model to investigate the evolution of these anomalies and test the efficiency of existing and novel treatments to cros