On the cause of multiple sclerosis: Molecular mechanisms regulating myelin biogenesis

Marjolein Bijlard

On the cause of multiple sclerosis: Molecular mechanisms regulating myelin biogenesis

Marjolein Bijlard

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Hoe myeline wordt gemaakt en hoe die kennis van nut kan zijn om een effectieve therapie voor MS te ontwikkelen.

Myeline, de vette isolatielaag rondom zenuwcellen, raakt bij multiple sclerose (MS)-patiënten beschadigd door onder andere ontstekingsreacties. Die beschadigingen worden op den duur niet meer hersteld. Om te begrijpen waarom dat niet meer gebeurt, is het belangrijk te weten hoe in normale situaties de myelinemembranen worden gevormd. Met die kennis verwachten we gereedschap in handen te krijgen om de aanmaak van nieuw myeline in de aangetaste gebieden (‘laesies’) weer in gang te zetten en zo de beschermende myeline-laag weer op te bouwen.
In dit onderzoek hebben we o.a. inzicht gekregen in de wijze waarop de twee belangrijkste myeline eiwitten, MBP en PLP, beïnvloed kunnen worden in de aanmaak van myeline. Zo hebben we bijvoorbeeld waargenomen dat wanneer de aanmaak van syntaxine 4, een bekend ankereiwit in transportprocessen, in voorlopercellen van oligodendrocyten wordt geblokkeerd, er geen MBP eiwit meer wordt ingebouwd in het myeline. Ook hebben we vastgesteld dat de transportroute van PLP verandert, wanneer in rijpere oligodendrocyten MAL eiwit – een transport-regulerend eiwit – wordt gemaakt. Maar ook factoren van buiten de cel hebben invloed op de aanmaak van myeline. Zoals de ontstekingsmediator TNFα, aanwezig in MS laesies, die ervoor zorgt dat het geraamte van de cel (cytoskelet) in volwassen oligodendrocyten dusdanig wordt aangetast, dat het MBP eiwit niet meer volledig in myeline terechtkomt.
Dit onderzoek geeft nieuw en gedetailleerd inzicht in de moleculaire mechanismen die de lokalisatie van de belangrijkste myeline componenten reguleren, en daarmee de myeline aanmaak. Deze resultaten kunnen in de toekomst helpen om nieuwe behandelingen voor MS te ontwikkelen.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Hoekstra, Dick, Supervisor Baron, Wia, Co-supervisor
Datum van toekenning	4-apr.-2016
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-90-367-8698-0
Elektronische ISBN's	978-90-367-8697-3
Status	Published - 2016

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Title and contents Final publisher's version, 277 KB
Chapter 1 Final publisher's version, 727 KB
Chapter 2 Final publisher's version, 2,4 MB
Chapter 3 Final publisher's version, 2,1 MB
Chapter 4 Final publisher's version, 2,59 MB
Chapter 5 Final publisher's version, 3,5 MB
Chapter 6 Final publisher's version, 402 KB
References Final publisher's version, 1,14 MB
Nederlandse samenvattingFinal publisher's version, 640 KB
Dankwoord Final publisher's version, 249 KB
Complete thesisFinal publisher's version, 8,5 MB
PropositionsFinal publisher's version, 64 KB

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@phdthesis{72c60bca0f514116ab19cfd9176b3b97,

title = "On the cause of multiple sclerosis: Molecular mechanisms regulating myelin biogenesis",

abstract = "On the assembly of myelin and how such knowledge may aid in improving the therapeutic treatment of MSMyelin, the fatty insulation layer around nerve cells, sustains damage in patients suffering from multiple sclerosis (MS), among others due to inflammation. Importantly, eventual regeneration of myelin fails. To understand the underlying mechanism, it is important to know how the myelin membranes are formed in {\textquoteleft}normal{\textquoteright} conditions. This knowledge will be imperative to develop novel molecular tools for {\textquoteleft}rebuilding{\textquoteright} the protective myelin coat in MS lesions. Among others, this research project has revealed new insight as to how the two major myelin proteins, MBP and PLP, can be affected in the process of myelin assembly. For example, when the production of syntaxin 4, a well-known anchor protein in transport processes, is blocked in the precursor cells of oligodendrocytes, the production of MBP halts. We also discovered that the transport of PLP changes when in more mature oligodendrocytes, MAL protein – a transport-regulating protein - is expressed. Furthermore, factors from outside of the cell may also affect the production of myelin. For example, the inflammation mediator TNFα, present in MS lesions, influences the cytoskeleton in such a way that MBP fails to reach the myelin.This study provides new and detailed insight into molecular mechanisms that regulate the localization of the main myelin components and hence, the assembly of myelin. These results will be beneficial in the development of new therapeutic treatments for MS.",

author = "Marjolein Bijlard",

year = "2016",

language = "English",

isbn = "978-90-367-8698-0",

publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

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TY - BOOK

T1 - On the cause of multiple sclerosis

T2 - Molecular mechanisms regulating myelin biogenesis

AU - Bijlard, Marjolein

PY - 2016

Y1 - 2016

N2 - On the assembly of myelin and how such knowledge may aid in improving the therapeutic treatment of MSMyelin, the fatty insulation layer around nerve cells, sustains damage in patients suffering from multiple sclerosis (MS), among others due to inflammation. Importantly, eventual regeneration of myelin fails. To understand the underlying mechanism, it is important to know how the myelin membranes are formed in ‘normal’ conditions. This knowledge will be imperative to develop novel molecular tools for ‘rebuilding’ the protective myelin coat in MS lesions. Among others, this research project has revealed new insight as to how the two major myelin proteins, MBP and PLP, can be affected in the process of myelin assembly. For example, when the production of syntaxin 4, a well-known anchor protein in transport processes, is blocked in the precursor cells of oligodendrocytes, the production of MBP halts. We also discovered that the transport of PLP changes when in more mature oligodendrocytes, MAL protein – a transport-regulating protein - is expressed. Furthermore, factors from outside of the cell may also affect the production of myelin. For example, the inflammation mediator TNFα, present in MS lesions, influences the cytoskeleton in such a way that MBP fails to reach the myelin.This study provides new and detailed insight into molecular mechanisms that regulate the localization of the main myelin components and hence, the assembly of myelin. These results will be beneficial in the development of new therapeutic treatments for MS.

AB - On the assembly of myelin and how such knowledge may aid in improving the therapeutic treatment of MSMyelin, the fatty insulation layer around nerve cells, sustains damage in patients suffering from multiple sclerosis (MS), among others due to inflammation. Importantly, eventual regeneration of myelin fails. To understand the underlying mechanism, it is important to know how the myelin membranes are formed in ‘normal’ conditions. This knowledge will be imperative to develop novel molecular tools for ‘rebuilding’ the protective myelin coat in MS lesions. Among others, this research project has revealed new insight as to how the two major myelin proteins, MBP and PLP, can be affected in the process of myelin assembly. For example, when the production of syntaxin 4, a well-known anchor protein in transport processes, is blocked in the precursor cells of oligodendrocytes, the production of MBP halts. We also discovered that the transport of PLP changes when in more mature oligodendrocytes, MAL protein – a transport-regulating protein - is expressed. Furthermore, factors from outside of the cell may also affect the production of myelin. For example, the inflammation mediator TNFα, present in MS lesions, influences the cytoskeleton in such a way that MBP fails to reach the myelin.This study provides new and detailed insight into molecular mechanisms that regulate the localization of the main myelin components and hence, the assembly of myelin. These results will be beneficial in the development of new therapeutic treatments for MS.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-8698-0

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -

On the cause of multiple sclerosis: Molecular mechanisms regulating myelin biogenesis

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