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dc.contributor.author
Dimas, Penelope Maria
dc.contributor.supervisor
Suter, Ulrich
dc.contributor.supervisor
Franklin, Robin J. M.
dc.contributor.supervisor
Kovacs, Werner
dc.contributor.supervisor
Stoeckli, Esther
dc.date.accessioned
2020-11-02T09:54:05Z
dc.date.available
2017-10-16T15:02:02Z
dc.date.available
2017-10-17T06:48:07Z
dc.date.available
2020-11-02T09:54:05Z
dc.date.issued
2017-10
dc.identifier.uri
http://hdl.handle.net/20.500.11850/196115
dc.identifier.doi
10.3929/ethz-b-000196115
dc.description.abstract
A variety of pathological conditions of the central nervous system (CNS) are associated with demyelination and loss of myelinating oligodendrocytes, e.g. spinal cord injury, stroke, and primary demyelinating diseases such as multiple sclerosis (MS). Common to all of these pathologies is the intrinsic, yet variable, capacity of the CNS to regenerate damaged myelin sheaths, resulting in the restoration of saltatory conduction and neuroprotection. Although remyelination can be initially extensive, it characteristically fails in long-standing, chronic demyelinating pathologies, such as MS. Remyelination in the CNS is primarily mediated by a pool of adult progenitor cells, the oligodendrocyte progenitor cells (OPCs). Upon demyelination, these highly proliferative and migratory progenitors are activated and recruited to the lesion site, where they differentiate into oligodendrocytes and form new myelin sheaths around denuded axons. Proliferation of adult OPCs and subsequent differentiation into myelinating cells during remyelination requires a tremendous increase in cell size and cellular membranes, hence calling for a vast surge in lipid availability. Fatty acids are the primary apolar building blocks for complex membrane lipids, and thus myelin itself. Moreover, fatty acids are critical to a variety of fundamental cellular processes, including membrane targeting of proteins, energy storage, cell signaling and transcriptional regulation. Most cells are thought to primarily rely on uptake to maintain their fatty acids pool, but highly metabolically active and proliferative, e.g. precursor/stem cells are strongly dependent on de novo synthesis mediated by fatty acid synthase (FASN). The multifunctional enzyme FASN is strictly required for de novo synthesis of fatty acids, mostly palmitate. Tissue-specific ablation of FASN in various cell types has provided valuable insights into the diverse and largely cell type- specific functions of de novo fatty acid synthesis. Given the highly proliferative nature of OPCs and the tremendous demand for lipids towards membrane synthesis during remyelination, we hypothesized endogenous fatty acid synthesis in OPCs to be critical in these processes. To this end, we induced FASN depletion in adult OPCs to assess its requirement for OPC proliferation, differentiation, and remyelination, following experimental gliotoxin-induced demyelination. We show that FASN is very low expressed in OPCs, but strongly expressed in oligodendrocytes differentiated from adult OPCs during remyelination. Consistently, FASN-activity is dispensable for adult OPC proliferation and maintenance during remyelination. Most importantly, we found FASN activity is critical for efficient CNS remyelination, an effect that is at least in part dependent on the requirement of FASN-mediated de novo fatty acid synthesis for maintaining the adult OPC-derived oligodendrocyte population during remyelination. Our results add valuable information to the understanding of the regulation of the remyelination process in demyelinating conditions, a promising currently pursued drug target.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.rights.uri
http://rightsstatements.org/page/InC-NC/1.0/
dc.subject
Oligodendrocyte
en_US
dc.subject
myelin repair
en_US
dc.subject
FATTY ACID METABOLISM
en_US
dc.title
The Essential Role of de Novo Fatty Acid Synthesis in CNS Myelin Regeneration
en_US
dc.type
Doctoral Thesis
dc.rights.license
In Copyright - Non-Commercial Use Permitted
ethz.size
156 p.
en_US
ethz.code.ddc
DDC - DDC::5 - Science::570 - Life sciences
en_US
ethz.identifier.diss
24605
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::03367 - Suter, Ulrich / Suter, Ulrich
en_US
ethz.date.deposited
2017-10-16T15:02:03Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.date.embargoend
2020-10-18
ethz.rosetta.installDate
2017-10-17T06:48:40Z
ethz.rosetta.lastUpdated
2021-02-15T19:32:40Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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