Segnalo l’articolo Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Molecular Autism 2010, 1:15 doi:10.1186/2040-2392-1-15 Ozlem Bozdagi ([email protected]) Takeshi Sakurai ([email protected]) Danae Papapetrou ([email protected]) Xiaobin Wang ([email protected]) Dara L Dickstein ([email protected]) Nagahide Takahashi ([email protected]) Yuji Kajiwara ([email protected]) Mu Yang ([email protected]) Adam M Katz ([email protected]) Maria Luisa Scattoni ([email protected]) Mark J Harris ([email protected]) Roheeni Saxena ([email protected]) Jill L Silverman ([email protected]) Jacqueline N Crawley ([email protected]) Qiang Zhou ([email protected]) Patrick R Hof ([email protected]) Joseph D Buxbaum ([email protected]) leggibile integralmente al link http://www.molecularautism.com/content/pdf/2040-2392-1-15.pdf L’interesse per i geni e le proteine Shank è emerso con forza negli ultimi anni. Segnalo alcuni lavori a partire dal 2006 Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders Christelle M Durand1, Catalina Betancur2, Tobias M Boeckers3, Juergen Bockmann3, Pauline Chaste1, Fabien Fauchereau1,4, Gudrun Nygren5, Maria Rastam5, I Carina Gillberg5, Henrik Anckarsa¨ter5, Eili Sponheim6, Hany Goubran-Botros1, Richard Delorme1, Nadia Chabane7, Marie-Christine Mouren-Simeoni7, Philippe de Mas8, Eric Bieth8, Bernadette Roge´9, Delphine He´ron10, Lydie Burglen11, Christopher Gillberg5,12, Marion Leboyer2,13 & Thomas Bourgeron1,4, Nature Genetics 39, 25 - 27 (2006) Published online: 17 December 2006 | doi:10.1038/ng1933 http://www.nature.com/ng/journal/v39/n1/abs/ng1933.html Contribution of SHANK3 Mutations to Autism Spectrum Disorder Rainald Moessner,* Christian R. Marshall,* James S. Sutcliffe, Jennifer Skaug, Dalila Pinto, John Vincent, Lonnie Zwaigenbaum, Bridget Fernandez, Wendy Roberts, Peter Szatmari, and Stephen W. Scherer The American Journal of Human Genetics Volume 81 December 2007, www.ajhg.org 22q13.3 Deletion Syndrome: Clinical and Molecular Analysis Using Array CGH Dhar SU, del Gaudio D, German JR, Peters SU, Ou Z, Bader PI, Berg JS, Blazo M, Brown CW, Graham BH, Grebe TA, Lalani S, Irons M, Sparagana S, Williams M, Phillips III JA, Beaudet AL, Stankiewicz P, Patel A, Cheung SW, Sahoo T., AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2010 152A:573–581. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation Simone Berkel1, Christian R Marshall2, Birgit Weiss1, Jennifer Howe2, Ralph Roeth1, Ute Moog3, Volker Endris1, Wendy Roberts4, Peter Szatmari5, Dalila Pinto2, Michael Bonin6, Angelika Riess6, Hartmut Engels7, Rolf Sprengel8, Stephen W Scherer2,9 & Gudrun A Rappold1, Nature Genetics VOLUME 42 | NUMBER 6 | JUNE 2010, 489-491 Another piece of the autism puzzle Matthew W State volume 42 | number 6 | JUNE 2010 | nature genetics, 478 Questi lavori riportano la presenza di mutazioni, o delezioni, dei geni shank in soggetti con disturbi dello spettro autistico e/o ritardo mentale. Ma l’associazione è casuale o più che casuale? Se più che casuale, è causale, ovvero sufficiente da sola a provocare la sindrome, o solo fattore di suscettibilità? Era plausibile che l’associazione fosse quanto meno più che casuale per quanto si sapeva della funzione delle proteine codificate dagli SHANK nello sviluppo, nella struttura e nella funzione delle sinapsi. “SHANKs are among the most abundant scaffolding proteins in the postsynaptic density. Together with HOMER, they were recently shown to form a mesh-like matrix structure that is required for the structural integrity of the dendritic spines and serves as an ‘assembly platform’ for other proteins residing within the postsynaptic density. It is therefore conceivable that the SHANK proteins play an important role as central organizers of the postsynaptic density. (Berkel1 2010)” “SHANK2 is one of three homologous scaffolding proteins (SHANK1–3) highly expressed at the postsynaptic density (PSD), a functionally specialized, electrondense structure found at the postsynaptic membrane in excitatory, glutamatergic synapses. there is already evidence that these interactions are required for normal synaptic function, that they mediate plasticity and that they ensure an appropriate balance of inhibitory and excitatory synapses6,7. (State 2010)” “Shank proteins are believed to function as master organizers of the postsynaptic density (PSD), owing to their ability to form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins present in dendritic spines and PSDs6,( Durand 2006) » Ma gli stessi articoli riportano molti dubbi e molti punti interrogativi. “We know little about the molecular mechanisms that initiate or stabilize synaptic growth and the molecules that lead to cytoskeletal rearrangements during synapse formation or remodelling (Berkel1, 2010)” “The precise contribution of these proteins, and their varied isoforms, to nervous system development and function remains a matter for investigation , many questions remain, among them: what are the distinct functions of SHANK2 and SHANK3 and why do heterozygous mutations in either lead to highly penetrant behavioral phenotypes? (State 2010)” Il lavoro di Bozdagi et al ( tra gli autori c’è anche Maria Luisa Scattoni dell’Istituto Superiori di Sanità) ha come scopo quello di dare una risposta a questi interrogativi. Per fare luce sul ruolo della proteina Shank 3 a livello sinaptico, il gruppo ha creato topi eterozigoti per mancanza del gene SHANK3 (mice with a disruption of the Shank3 gene) e ha esaminato le conseguenti alterazioni a livello sinaptico, messe poi in relazione con le deviazioni del comportamento sociale dei topi. (we saw evidence of social interaction and social communication deficits in these mice.) Da queste correlazioni si evince il ruolo delle protine Shank 3 e, di conseguenza, si rende plausibile un rapporto di causa-effetto tra alterazioni del gene, fini alterazioni della struttura e della funzione sinaptica e ritardi o anomalie dello sviluppo cognitivo e sociale Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. Electrophysiological studies of the mice showed a decrease in basal synaptic transmission in heterozygotes Shank3 heterozygous mice also showed a decrease in the density of GluR1- immunoreactive puncta, consistent with a reduction in AMPA receptor levels. reduction of both synaptic transmission and plasticity in the Shank3 heterozygotes would support a mechanism involving altered AMPA receptor trafficking. Haploinsufficiency of full-length Shank3 resulted in a decrease in synaptic transmission, altered functional and structural plasticity of synapses and reduced social behaviors. We observed reductions in glutamatergic synaptic transmission and plasticity, including deficits in AMPA receptor-mediated transmission and spine remodeling These results demonstrate the importance of Shank3 in synaptic function, ultimately leading to behavioral changes, which may be relevant to the symptoms in individuals with SHANK3 mutations. Gli autori indicano anche direzioni per futuri approcci terapeutici in quanto le alterazioni da loro evidenziate possono indicare target per lo sviluppo di farmaci The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes. The results are consistent with an important role for SHANK3 in synaptic function and plasticity and implicate specific pathways as potential therapeutic targets for SHANK3-haploinsufficiency syndromes. Recently, the field has begun to see the evaluation of therapies targeted to etiology (that is, “personalized medicine”) using models of neurodevelopmental disorders including fragile X, tuberous sclerosis, and Rett syndromes (see, for example, [61-64]). The use of model systems such as the Shank3-deficient mice reported here could lead to similar advances in the case of SHANK3-haploinsufficiency sindrome One interesting outcome of the current study is that compounds that enhance glutamatergic transmission, including those that specifically enhance AMPA transmission (AMPAkines) could possibly represent therapeutic approaches in these conditions. .