Notch-1 signaaltransductie en oligodendrocyten dysfunctie in amyotrofe laterale sclerose

Caroline Eykens
Het onderzoek naar ALS in een stroomversnelling?LEUVEN - ‘Wat wanneer amyotrofe laterale sclerose (ALS) je lichaam binnensluipt?’. Met deze slogan kreeg de zenuwspierziekte ALS de jongste maanden heel wat media-aandacht. Het antwoord is helaas niet erg hoopgevend. De aandoening is doorgaans fataal 2 à 5 jaar na diagnose aangezien er nog geen doeltreffende therapie beschikbaar is. Wat is nu de precieze oorzaak van ALS? Dat houdt het biomedisch onderzoek al ettelijke jaren bezig. Een eenduidige verklaring hiervoor heeft men echter nog niet gevonden.

Notch-1 signaaltransductie en oligodendrocyten dysfunctie in amyotrofe laterale sclerose

Het onderzoek naar ALS in een stroomversnelling?

LEUVEN - ‘Wat wanneer amyotrofe laterale sclerose (ALS) je lichaam binnensluipt?’. Met deze slogan kreeg de zenuwspierziekte ALS de jongste maanden heel wat media-aandacht. Het antwoord is helaas niet erg hoopgevend. De aandoening is doorgaans fataal 2 à 5 jaar na diagnose aangezien er nog geen doeltreffende therapie beschikbaar is. Wat is nu de precieze oorzaak van ALS? Dat houdt het biomedisch onderzoek al ettelijke jaren bezig. Een eenduidige verklaring hiervoor heeft men echter nog niet gevonden. In deze scriptie vestigden we de aandacht op cellen die belangrijk zijn voor de ondersteuning van de motorische zenuwcellen, meer bepaald de oligodendrocyten. Wat is er aan de hand met deze oligodendrocyten bij ALS?

ALS is een ongeneeslijke aandoening die gekenmerkt wordt door het selectief afsterven van de motorische zenuwcellen. Deze cellen zijn een belangrijke schakel in het overbrengen van commando’s van de hersenen naar de spieren. Ze zorgen ervoor dat onze spieren samentrekken wanneer actie ondernomen moet worden en verslappen in rust. Bijgevolg krijgen lijders aan de ziekte te maken met spierzwakte, onwillekeurige spierbewegingen en verlamming. ALS steekt meestal de kop op rond de leeftijd van 50 à 60 jaar en kan eender wie overkomen. De enige hulp die de medische wereld kan bieden, zijn middelen om de levenskwaliteit min of meer intact te houden tijdens het vreselijke aftakelingsproces. Uiteindelijk sterven de meeste patiënten enkele jaren na diagnose aan verstikking doordat de ademhalingsspieren verlamd raken. Door de sterk toegenomen levensverwachting en de hieruit voortvloeiende toename van een oudere bevolking, wordt onze samenleving alsmaar meer geconfronteerd met ALS. Hierdoor komen zorginstellingen onder druk te staan, maar ook de patiënten zelf en hun omgeving moeten heel wat leed verwerken. Daarom onderstrepen we hier het belang van neurobiologisch onderzoek in het vinden van nieuwe therapeutische aanknopingspunten voor deze ziekte.

Muizen dragen hun steentje bij

Wereldwijd worden ALS-muizen ingezet als  laboratoriumdieren met het oog op het verrichten van neurobiologisch onderzoek. Hiermee kan men namelijk meer inzicht verwerven in het ziektemechanisme dat aan de basis ligt van ALS. Deze muizen dragen net zoals sommige ALS-patiënten een erfelijke afwijking in het SOD1 gen. Door deze afwijking in het DNA sterven de motorische zenuwcellen geleidelijk aan af. Dat leidt zowel bij de patiënt als in het muismodel tot verlamming en uiteindelijk tot de dood. Studies hebben aangetoond dat alleen maar de aanwezigheid van het afwijkende SOD1 eiwit in de motorische zenuwcellen niet voldoende is om ALS te ontwikkelen. Tegelijk moet het eiwit ook aanwezig zijn in niet-neuronale cellen zoals astrocyten, microgliale cellen, oligodendrocyt voorlopercellen en oligodendrocyten (Figuur 1, bijlage).

Antennefunctie

Bij ALS-muizen en ALS-patiënten sterven de oligodendrocyten af nog voor de ziekte doorbreekt. Oligodendrocyten zijn zenuwcellen met een dubbele functie. Enerzijds voorzien ze de zenuwuitlopers van een vetachtig omhulsel en verzekeren ze op deze manier een snelle prikkelgeleiding doorheen het centraal zenuwstelsel (Figuur 2 (①), bijlage). Anderzijds bevoorraden ze de motorische zenuwcellen met de nodige voedingsstoffen via transportertjes (Figuur 2 (②), bijlage).  De afgestorven oligodendrocyten worden vervangen door nieuwe oligodendrocyten, maar bij ALS werken deze niet zoals het hoort. Aangezien oligodendrocyten niet kunnen delen, worden de nieuwe oligodendrocyten gevormd uit een reservoir van voorlopercellen (Figuur 3, bijlage). De Notch-1 receptor, vergelijkbaar met een soort antenne op de cel die signalen ontvangt en verzendt, is aanwezig op deze voorlopercellen. Men vermoedt dat deze receptor de uitgroei van oligodendrocyt voorlopercellen tot volwassen oligodendrocyten verhindert. Daarom vroegen we ons af of een ontregeling van de Notch-1 receptor bijdraagt tot de slechte uitgroei van de oligodendrocyt voorlopercellen bij ALS. Om deze hypothese te staven, onderzochten we of de verwijdering van de Notch-1 receptor bij ALS-muizen een gunstig effect zou kunnen hebben op het ziekteproces.

Weg met Notch-1

We weten dus dat bij ALS de oligodendrocyten niet goed werken. Zal verwijdering van de Notch-1 receptor de functie van deze cellen verbeteren? Onderzoek wees uit dat ALS-muizen met een gedaalde hoeveelheid van de Notch-1 receptor, een stijging van MBP en MCT-1 vertoonden in het ruggenmerg, in vergelijking met de ALS-muizen waarin de receptor normaal aanwezig was (Figuur 4, bijlage). Vermits beide eiwitten een idee geven over de werking van de oligodendrocyten, wijst deze waarneming op een betere werking van de oligodendrocyten na Notch-1 verwijdering bij ALS.

Het eerste belangrijke symptoom in het ziekteverloop van ALS is dat de uitlopers van de motorische zenuwcellen zich terugtrekken uit de spier die ze bezenuwen. Kan Notch-1 verwijdering dat tegengaan? Onze resultaten suggereren van wel. Bij ALS-muizen waarin de Notch-1 receptor zo goed als afwezig was, maakte een groter aantal uitlopers van de motorische zenuwcellen contact met de kuitspier in vergelijking met gewone ALS-muizen (Figuur 5, bijlage). Dat werd ook vertaald in een betere prikkelgeleiding in de spier, zoals we konden waarnemen in de resultaten van onze elektromyografie (Figuur 6, bijlage). Hierbij wordt het principe van vraag en antwoord toegepast. De motorische zenuwcellen krijgen een elektrische schok toegediend en er wordt gemeten hoe groot de reactie van de spier hierop is (Figuur 7, bijlage).

Ziekte afremmen

Samengevat kunnen we stellen dat verwijdering van de Notch-1 receptor de werking van de oligodendrocyten verbetert bij ALS. Ook de communicatie tussen de motorische zenuwcellen en de spiervezels verloopt efficiënter. De Notch-1 receptor zou dus een mogelijk therapeutisch aangrijpingspunt kunnen vormen in de strijd tegen deze vreselijke aandoening. Met deze ontdekking kunnen we ALS waarschijnlijk niet genezen, maar het geeft ons wel de mogelijkheid om de ziekte trachten af te remmen. Notch-1 is een fascinerende receptor die ons weer een stapje verder helpt in het neurobiologisch onderzoek naar ALS.

 

‘‘Verwijdering van de Notch-1 receptor heeft een gunstig effect op het ziekteverloop van ALS. Hopelijk kan deze ontdekking bijdragen tot het afremmen van deze ziekte’’

 

  1. Heeft u na het lezen van dit artikel meer interesse gekregen in het huidige onderwerp? Dan is het zeker aan te raden om de integrale thesis ‘Notch-1 signaaltransductie en oligodendrocyten dysfunctie in amyotrofe laterale sclerose’ te lezen. Deze werd bekroond met de eerste prijs voor de ’Beste masterproef biomedische wetenschappen 2013’(KU Leuven).

 

                                                                                                                                Caroline EYKENS

 

 

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Biomedische wetenschappen
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2013
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