[autismo-biologia] aminoacidi a catena ramificata e autismo

[daniela a autismo33.it]

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
gaia.novarino a ist.ac.at


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
gaia.novarino a ist.ac.at
Dr. Elisabeth Guggenberger
Media Relations Manager
E-Mail: elisabeth.guggenberger a ist.ac.at 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