E’ stato pubblicato il primo dicembre scorso l’articolo Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder Dora C. Tărlungeanu Elena Deliu Christoph P. Dotte Majdi Kara Philipp Christoph Janiesch Mariafrancesca Scalise Michele Galluccio Mateja Tesulov Emanuela Morelli Fatma Mujgan Sonmez Kaya Bilguvar Ryuichi Ohgaki Yoshikatsu Kanai Anide Johansen Seham Esharif Tawfeg Ben-Omran Meral Topcu Avner Schlessinger Cesare Indiveri Kent E. Duncan Ahmet Okay Caglayan Murat Gunel Joseph G. Gleeson Gaia Novarino15, Cell, Volume 167, Issue 6, p1481–1494.e18, 1 December 2016 http://www.cell.com/cell/fulltext/S0092-8674(16)31534-3 I dati salienti del lavoro di cui l’articolo dá il resoconto sono i seguenti - il gene Slc7a5 é critico per mantenere nel cervello livelli normali di aminoacidi a catena ramificata (branched-chain amino acid: BCAA ) - un deficit di BCAA cerebrali innesca nei topi delle anomalie neurocomportamentali - I pazienti con mutazioni di Slc7a5 hanno disturbi dello spettro autistico e ritardi motori - il comportamento anomalo del topo mutante per Slc7a5 é parzialmente corretto da iniezioni di aminoacidi a catena ramificata. L’articolo é di grande interessa perché - scopre un nuovo gene la cui mutazione é causa di autismo. - di questo gene si conosce la funzione (la sua mancanza impedisce l’ingresso di BCAA nel cervello). - nel topo adulto si sono avuti miglioramenti del comportamento con la somministrazione intracerebrale di aminoacidi a catena ramificata. La mutazione associata a spettro autistico é stata riscontrata in figli di coppie consanguinee. A questo punto si pone il solito quesito. Se si trovasse una terapia efficace e praticabile nell’uomo, é plausibile pensare che la stessa terapia funzionerebbe anche in altre condizioni, oltre che nella mutazione di Slc7a5? Ho posto la domanda ad una coautrice del lavoro, Gaia Novarino, che mi ha inviato la seguente risposta Gentile Daniela, grazie per il suo interesse nella nostra ricerca. Per quanto riguarda la sua domanda rispetto al gruppo più’ ampio di soggetti, la nostra ipotesi e’ che benché’ ci siano molte diverse mutazioni genetiche che causano disturbi dell spettro autistico e altre malattie del neurosviluppo, in diversi casi pensiamo sia possibile trovare delle analogie funzionali e che quindi soggetti con mutazioni in geni diversi potrebbero presentare lo stesso meccanismo patofisiologico. Per esempio qualche anno fa abbiamo individuato pazienti con mutazioni in un altro gene (BCKDK) che causa ASD. Il meccanismo che conduce all’autismo in questi pazienti ipotizziamo sia esattamente lo stesso di quello di pazienti che hanno mutazioni in questo nuovo gene (SLC7A5). Inoltre i dati che stiamo acquisendo ci fanno ritenere di poter trovare analogie con forme di autismo dovute ad altre mutazioni genetiche ma con un simile meccanismo di azione. Rimango a vostra disposizione nel caso vi interessasse avere altre informazioni. Cordiali Saluti, Gaia Gaia Novarino, PhD Assistant Professor Institute of Science and Technology Austria Am Campus 1 A-3400 Klosterneuburg Ph.0043224390005901 [email protected] Ed ecco il comunicato stampa dell’Institute of Science and Technology (IST Austria) Klosterneuburg, November 30, 2016 New form of autism found An international team of researchers led by scientists at IST Austria identified a new form of syndromic autism • Study published in Cell Autism spectrum disorders affect around one percent of the world’s population and are characterized by a range of difficulties in social interaction and communication. In a new study published in Cell today, a team of researchers led by Gaia Novarino, Professor at IST Austria, has identified a new genetic cause of ASD. Gaia Novarino explains why this finding is significant: “There are many different genetic mutations causing autism, and they are all very rare. This heterogeneity makes it difficult to develop effective treatments. Our analysis not only revealed a new autism-linked gene, but also identified the mechanism by which its mutation causes autism. Excitingly, mutations in other genes share the same autism-causing mechanism, indicating that we may have underscored a subgroup of ASDs.” “The identification of novel genes, especially in heterogeneous diseases such as autism, is difficult. However, as result of a collaborative effort, we were able to identify mutations in a gene called SLC7A5 in several patients born to consanguineous marriages and diagnosed with syndromic autism”, points out Dr. Caglayan, Chairman of the Department of Medical Genetics in the School of Medicine at İstanbul Bilim University in Turkey and co-author of the study. SLC7A5 transports a certain type of amino acids, the so-called branched-chain amino acids (BCAA), into the brain. To understand how mutations of SLC7A5 lead to autism, the researchers studied mice in which SLC7A5 is removed at the barrier between the blood and the brain. This reduces the levels of BCAAs in their brain, and interferes with protein synthesis in neurons. Consequently, the mice show reduced social interaction and other changes in their behavior, which are also observed in other autism mouse models. In a previous study, Gaia Novarino and colleagues identified a mutation in a gene that is involved in the breakdown of these same amino acids in several patients with ASD, intellectual disability and epilepsy. “Of course, not all genes causing autism affect amino acid levels, and these forms of autism are unarguably very rare, but it is possible that even more autism- causing genes fall in this group.” explains Gaia Novarino. Notably, the researchers were able to treat some of the neurological abnormalities in the adult mice missing SLC7A5 at the blood-brain barrier. After delivering BCAAs straight into the mice’s brains for three weeks, the authors observed an improvement in behavioral symptoms. Dora Tarlungeanu, PhD student in Gaia Novarino’s group and first author of the study, is excited about the outlook this result gives: “Our research found a potential treatment for certain symptoms presented in this form of ASD in mice but translation into a treatment for ASD patients will require many years of additional research.” The researchers’ results contrast with the idea that ASDs are always irreversible conditions. The way they treated symptoms in the mice can, of course, not directly be used in humans. But they show that some of the neurological complications presented by mice missing Slc7a5 can be rescued, and so it is possible that – eventually – patients may be treated as well. Image: A healthy blood-brain barrier (left side) where a transporter allows certain amino acids into the brain is compared to the case where the transporter is missing (right side). When the transporter is present the mice actively move around and socially interact with each other. This is measured by the scientists by tracking the movements of the mice (locomotion pattern in the middle) as well as their positions (map in the lower right). When the transporter is absent, the mice move less and tend to stay apart (seen as the two separate red dots in the map) demonstrating less interest for social contact - a measure of autism-associate behavior. Contact: Gaia Novarino, PhD Assistant Professor [email protected] Dr. Elisabeth Guggenberger Media Relations Manager E-Mail: [email protected] Tel: +43 2243 9000 1199 Mobile: +43 (0)664 88326170 IST Austria The Institute of Science and Technology (IST Austria) is a PhD granting research institution located in Klosterneuburg, 18 km from the center of Vienna, Austria. Inaugurated in 2009, the Institute is dedicated to basic research in the natural and mathematical sciences. IST Austria employs professors on a tenure-track system, postdoctoral fellows, and doctoral students at its international graduate school. While dedicated to the principle of curiosity-driven research, the Institute owns the rights to all scientific discoveries and is committed to promote their use. The first president of IST Austria is Thomas A. Henzinger, a leading computer scientist and former professor at the University of California in Berkeley, USA, und der EPFL in Lausanne, Switzerland. www.ist.ac.at