Medicina in Biblioteca

Weblog della Biblioteca Medica "PINALI" Università degli Studi di Padova

  • Categorie

  • Archivi

  • Pagine

  • Inserisci il tuo indirizzo e-mail per iscriverti a questo blog e ricevere notifiche di nuovi messaggi per e-mail.

    Segui assieme ad altri 412 follower

  • QR Code Blog

    Scarica e installa il software direttamente dal telefonino: sito i-nigma; fotografa il codice e avrai le news dal blog sempre con te.


  • Seguimi su Libero Mobile

  • sito internet

  • Sito d'argento

SLA: Nuovo possibile approccio terapeutico.

Posted by giorgiobertin su aprile 13, 2017

Uno studio condotto da ricercatori della Stanford University School of Medicine ha rivelato un possibile nuovo approccio terapeutico per la sclerosi laterale amiotrofica (SLA), una malattia neurodegenerativa progressiva.

In particolare il team di Stanford guidato ha eseguito una serie di esperimenti che dimostrano che la soppressione di una certa proteina in un modello murino di SLA, o morbo di Lou Gehrig, potrebbe notevolmente estendere la durata della vita dell’animale. Come riportato nello studio, nessuno dei topi non trattati è vissuto più a lungo di 29 giorni, mentre i topi trattati hanno vissuto più di 400 giorni. La pubblicazione è stata fatta sulla rivista “Nature“.

Gitler
Aaron Gitler and his colleagues found that suppressing a protein in mice with a form of ALS allowed them to live longer and improved their motor function.

Un indicatore della SLA, nonché altre malattie neurodegenerative, sono dei ciuffi di proteina nel cervello. Nei paienti con SLA, questi grumi o aggregati, sono costituiti da una proteina chiamata TDP-43. Eliminare le TDP-43 e gli aggregati TDP-43 potrebbe essere un buon modo per prevenire o curare la SLA. “Sapevano, da studi precedenti che una seconda proteina, atassina 2, aiuta la sopravvivenze delle cellule tossiche aggregate TDP-43. A differenza di TDP-43, atassina 2 non è essenziale per la sopravvivenza di una cellula, e questo rende la proteina un obiettivo terapeutico ragionevole“. – afferma il prof. Aaron Gitler.

Negli animali trattati è stato sperimentato un tipo di farmaco DNA-like, progettato per bloccare la produzione di atassina 2. Somministrato nel sistema nervoso dei topi con SLA ha permesso loro di mantenersi in salute molto più a lungo rispetto ai topi affetti da SLA trattati con un placebo.
Il targeting atassina 2 potrebbe essere una strategia terapeutica ampiamente efficace.

La SLA è una malattia in cui le cellule nervose del cervello e del midollo spinale degenerano, questo porta al deperimento dei muscoli. I pazienti perdono gradualmente la capacità di muoversi, parlare, mangiare o respirare, che spesso conduce alla paralisi e alla morte in due a cinque anni.

Leggi abstract dell’articolo:
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice
Lindsay A. Becker, Brenda Huang, Gregor Bieri, Rosanna Ma, David A. Knowles, Paymaan Jafar-Nejad, James Messing, Hong Joo Kim, Armand Soriano, Georg Auburger, Stefan M. Pulst, J. Paul Taylor, Frank Rigo & Aaron D. Gitler
Nature (2017)  Published online 12 April 2017 doi:10.1038/nature22038

Fonte: Stanford University School of Medicine

Annunci

Una Risposta to “SLA: Nuovo possibile approccio terapeutico.”

  1. DANIELA PELOTTI said

    What kick-starts the aggregation of pathological proteins in neurodegenerative disease? In the October 6 Scientific Reports, researchers led by Robert Friedland at the University of Louisville School of Medicine, Kentucky, present more evidence that microorganisms might play a role. Feeding aging rats with Escherichia coli that produces its own amyloid protein accelerated the deposition of α-synuclein in both the gut and the brain, they report. The new data bolster the hypothesis that Parkinson’s disease can start in the gut, and that amyloidogenic proteins can “cross-seed,” a process where one type of misfolded protein causes another to misfold. “There are now substantial reasons to believe that our microbiota may influence neurodegenerative diseases,” Friedland told Alzforum. Because the composition of the gut microbiome can be altered by diet or other environmental factors, this research might open up new therapeutic approaches, he suggested.

    Others found the data intriguing as well. “The possibility of such cross-seeding events in the gut … may offer a novel target for prevention and/or pharmacological treatment. However, additional studies are needed to understand these molecular interactions, including identifying the exact nature of the propagating α-synuclein species,” Martin Ingelsson and Joakim Bergström at Uppsala University, Sweden, wrote to Alzforum (see full comment below). Jeffrey Kordower at Rush University, Chicago, noted, “The idea that microbiota influence brain function has been around for many years, but now it’s accumulating empirical data. This is an excellent, exciting paper that will stimulate more research.”

    Cross-Seeding?
    Worms fed on bacteria that produce amyloid (left) developed many more and larger α-synuclein inclusions (green) than did worms eating control bacteria (right). [Courtesy of Chen et al., Scientific Reports.]
    The concept that microbiota could initiate degeneration has been gradually taking hold. Heiko Braak and Kelly del Tredici at the University of Ulm, Germany, first documented in 2003 how Parkinson’s pathology might begin in intestinal neurons, and from there work its way up to the brain, perhaps triggered by a pathogen such as a virus (see July 2011 series). A recent study from Finland tied differences in the gut microbiome to a diagnosis of Parkinson’s as well as the severity of movement problems in patients (see Scheperjans et al., 2015). Pathogens have also been implicated in Alzheimer’s disease. Researchers at Massachusetts General Hospital recently reported that Aβ’s normal function is to fight infection by trapping microbes in its fibrils, suggesting that this process might initiate pathological aggregation (see May 2016 news). In keeping with this, antibiotic treatment lessens amyloid pathology in AD model mice (see Minter et al., 2016).

    Friedland wondered if bacteria might stimulate neurodegenerative pathology through cross-seeding. Many bacteria found in people produce amyloids, and these proteins possess structural similarities to human pathological aggregates (see Larsen et al., 2007; Hufnagel et al., 2013; Friedland, 2015). Other studies have shown that different pathological proteins can stimulate each other’s aggregation, such as prions and TDP-43 triggering Aβ fibrillization, and α-synuclein seeding tau tangles (see Apr 2010 news; Jul 2013 news; Sep 2014 news).

    To test the effect of bacterial amyloid, second author Vilius Stribinskis turned to E. coli, which make an amyloidogenic protein called curli. Stribinskis and colleagues squirted a solution containing this bacteria into the mouths of 2-year-old wild-type rats once per week for two to three months. About one dozen rats received wild-type E. coli, another dozen swallowed mutant E. coli that lacked the ability to make curli, and nine more rats received vehicle only. When the animals were sacrificed and analyzed, those that had ingested normal E. coli had about 10 times more α-synuclein deposits in intestinal neurons, and about 50 percent more in hippocampal and striatal neurons, than the other two groups. Notably, the gut deposits dissolved upon treatment with proteinase K, suggesting they were not aggregated, whereas hippocampal α-synuclein deposits resisted this treatment. Inflammation also surged in the brains of rats that ate wild-type E. coli, with markers of microgliosis and astrogliosis up 50 to 100 percent. The paper does not report if any bacteria colonized the brain.

    Would the same thing occur in animal models of neurodegenerative disease? First author Shu Chen at Case Western Reserve University, Cleveland, fed wild-type and mutant E. coli to roundworms that expressed fluorescently tagged human α-synuclein in their body wall muscles. Worms that ate wild-type E. coli for three days developed about twice as many α-synuclein deposits in their muscles as did those eating control bacteria, again supporting the idea that bacterial amyloid can initiate deposition (see image above).

    How curli amyloid stimulates α-synuclein aggregation is not yet clear, but Friedland favors the idea that it occurs through cross-seeding and subsequent propagation of misfolded proteins from the gut to the brain through the vagus nerve. Notably, one of the first brain regions to succumb to Parkinson’s pathology is the dorsal motor nucleus of the vagus nerve in the medulla. In ongoing work, Friedland is testing whether these α-synuclein deposits affect behavior in aged rats. He is also examining how bacterial amyloids affect aggregation of other proteins in mouse models of different neurodegenerative diseases.

    Friedland will also pursue studies in people. He is studying differences in the bacterial population in Parkinson’s patients, and also looking at how common bacterial amyloids are in the human body. One previous study reported the presence of curli aggregates in people, but the subject has received almost no other investigation, Friedland noted (see Bokranz et al., 2005).

    Kordower suggested it would be interesting to track the time course of α-synuclein deposition in rats, to see if it follows anatomical pathways through the body and brain. He also wonders whether neuroinflammation precedes or trails aggregation. “That is fertile ground for future studies,” he noted. Overall, he found the work particularly exciting because it showed robust acceleration of α-synuclein deposition in wild-type rats, hinting this could be a mechanism for sporadic disease. The microbiome might contribute to many other neurodegenerative diseases besides Parkinson’s, Kordower suggested. The fact that amyloids can cross-seed many other types of aggregate might help explain the frequency of mixed pathology in brain disease, he speculated. “Studying the microbiome is one of the most exciting areas in neurodegenerative disease right now,” he told Alzforum.—Madolyn Bowman Rogers

Rispondi

Inserisci i tuoi dati qui sotto o clicca su un'icona per effettuare l'accesso:

Logo WordPress.com

Stai commentando usando il tuo account WordPress.com. Chiudi sessione / Modifica )

Foto Twitter

Stai commentando usando il tuo account Twitter. Chiudi sessione / Modifica )

Foto di Facebook

Stai commentando usando il tuo account Facebook. Chiudi sessione / Modifica )

Google+ photo

Stai commentando usando il tuo account Google+. Chiudi sessione / Modifica )

Connessione a %s...

 
%d blogger hanno fatto clic su Mi Piace per questo: