The identification of cell non-autonomous roles of astrocytes in neurodegeneration

Yixian Li

The identification of cell non-autonomous roles of astrocytes in neurodegeneration

Yixian Li

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Kennis over de pathogenese van ouderdomsgerelateerde neurodegeneratieve ziektes is belangrijk, aangezien er geen behandeling mogelijk is. Deze ziektes worden gekenmerkt door eiwitaggregatie in de hersenen en activatie van gliacellen. Gliacellen, zoals astrocyten en microglia, zijn belangrijke, niet-neuronale cellen in het CZS die neuronale functie en gezondheid ondersteunen.

In dit proefschrift zijn de meest voorkomende glia cellen, astrocyten, bestudeerd. We hebben responsen van astrocyten bestudeerd op neuronen die een aggregerend, neurodegeneratie-geassocieerd eiwit tot expressie brengen. We hebben de fruitvlieg, Drosophila melanogaster, gebruikt als een modelorganisme, vanwege de mogelijkheid om genexpressie in neuronen en astrocyten onafhankelijk van elkaar te manipuleren. De structuur en functie van het Drosophila CZS en astrocyten zijn vergelijkbaar met mensen.

Een aggregerend eiwit, geassocieerd met Spinocerebellar Ataxia 3 (SCA3polyQ78), werd tot expressie gebracht in Drosophila ogen of neuronen, resulterend in een degeneratief fenotype. Een screen in astrocyten werd uitgevoerd om genen te identificeren die bijdroegen aan SCA3polyQ78-geïnduceerde degeneratie. Eén geïdentificeerd gen was een geconserveerd NF-B gen, Relish. Remming van Relish in astrocyten vertraagde SCA3polyQ78-geïnduceerde neurodegeneratie. Vergelijkbare effecten werden gevonden in een Drosophila model voor de ziekte van Alzheimer.

Verder is bestudeerd hoe de activiteit van specifieke NF-B transcriptie factoren wordt gereguleerd, en gevonden dat dit gebeurt via specifieke calcineurine fosfatase isovormen. Calcineurine in astrocyten kan ook bijdragen aan SCA3polyQ78-geïnduceerde degeneratie. Dus, remming van specifieke calcineurine isovormen kan ook relevant zijn om een specifieke NF-B transcriptie factor te remmen bij neurodegeneratieve ziektes.

De bevindingen in dit proefschrift tonen de relevantie van astrocyten in neurodegeneratieve ziektes aan.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Sibon, Ody, Supervisor Dijkers, Pascal, Co-supervisor
Datum van toekenning	11-jun.-2018
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Gedrukte ISBN's	978-94-034-0765-4
Elektronische ISBN's	978-94-034-0766-1
Status	Published - 2018

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Title and contentsFinal publisher's version, 210 KB
Chapter 1Final publisher's version, 390 KB
Chapter 2Final publisher's version, 844 KB
Chapter 3Final publisher's version, 927 KB
Chapter 4Final publisher's version, 1,06 MB
Chapter 5Final publisher's version, 302 KB
SummaryFinal publisher's version, 140 KB
SamenvattingFinal publisher's version, 140 KB
AcknowledgementsFinal publisher's version, 364 KB
Complete thesisFinal publisher's version, 2,63 MB
PropositionsFinal publisher's version, 58,5 KB

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@phdthesis{56491fb07d45452aba0acd4c60253099,

title = "The identification of cell non-autonomous roles of astrocytes in neurodegeneration",

abstract = "Knowledge about the pathogenesis of age-related NDs is important, since there is no treatment available. Many age-related NDs are associated with protein aggregation and activation of glia cells. Glia cells, including astrocytes and microglia, are an important type of non-neuronal cells in the CNS to support neuronal function and health. This thesis focused on the most abundant glial cell, astrocytes. We examined responses of astrocytes to neurons that express an aggregation-prone, neurodegeneration-associated protein. We used the fruit fly Drosophila melanogaster as a model organism, because the available genetic tools allow simultaneous, independent manipulation of neurons and astrocytes. Many aspects of the structure and function of the Drosophila CNS and astrocytes are similar to humans. An aggregation-prone protein, associated with Spinocerebellar Ataxia 3 (SCA3polyQ78), was expressed in Drosophila eyes or neurons, resulting in a degenerative phenotype. A candidate screen was performed to identify genes in astrocytes that contributed to SCA3polyQ78-induced neurodegeneration. One of the identified genes in astrocytes was a conserved NF-kB gene, Relish. Relish inhibition in astrocytes delayed SCA3polyQ78-induced neurodegeneration. Similar observations were made in a Drosophila model for Alzheimer{\textquoteright}s disease. We further studied the upstream modulation of activity of distinct NF-kB transcription factors, and found that this occurs via distinct isoforms of the calcineurin phosphatase. Calcineurin genes in astrocytes can also contribute to SCA3polyQ78-induced neurodegeneration. Thus, modulating the activity of specific calcineurin isoforms may be of relevance in regulating the activity of a specific NF-kB in NDs.Together, findings in this thesis demonstrate the relevance of astrocytes in NDs.",

author = "Yixian Li",

year = "2018",

language = "English",

isbn = "978-94-034-0765-4",

publisher = "University of Groningen",

school = "University of Groningen",

}

TY - BOOK

T1 - The identification of cell non-autonomous roles of astrocytes in neurodegeneration

AU - Li, Yixian

PY - 2018

Y1 - 2018

N2 - Knowledge about the pathogenesis of age-related NDs is important, since there is no treatment available. Many age-related NDs are associated with protein aggregation and activation of glia cells. Glia cells, including astrocytes and microglia, are an important type of non-neuronal cells in the CNS to support neuronal function and health. This thesis focused on the most abundant glial cell, astrocytes. We examined responses of astrocytes to neurons that express an aggregation-prone, neurodegeneration-associated protein. We used the fruit fly Drosophila melanogaster as a model organism, because the available genetic tools allow simultaneous, independent manipulation of neurons and astrocytes. Many aspects of the structure and function of the Drosophila CNS and astrocytes are similar to humans. An aggregation-prone protein, associated with Spinocerebellar Ataxia 3 (SCA3polyQ78), was expressed in Drosophila eyes or neurons, resulting in a degenerative phenotype. A candidate screen was performed to identify genes in astrocytes that contributed to SCA3polyQ78-induced neurodegeneration. One of the identified genes in astrocytes was a conserved NF-kB gene, Relish. Relish inhibition in astrocytes delayed SCA3polyQ78-induced neurodegeneration. Similar observations were made in a Drosophila model for Alzheimer’s disease. We further studied the upstream modulation of activity of distinct NF-kB transcription factors, and found that this occurs via distinct isoforms of the calcineurin phosphatase. Calcineurin genes in astrocytes can also contribute to SCA3polyQ78-induced neurodegeneration. Thus, modulating the activity of specific calcineurin isoforms may be of relevance in regulating the activity of a specific NF-kB in NDs.Together, findings in this thesis demonstrate the relevance of astrocytes in NDs.

AB - Knowledge about the pathogenesis of age-related NDs is important, since there is no treatment available. Many age-related NDs are associated with protein aggregation and activation of glia cells. Glia cells, including astrocytes and microglia, are an important type of non-neuronal cells in the CNS to support neuronal function and health. This thesis focused on the most abundant glial cell, astrocytes. We examined responses of astrocytes to neurons that express an aggregation-prone, neurodegeneration-associated protein. We used the fruit fly Drosophila melanogaster as a model organism, because the available genetic tools allow simultaneous, independent manipulation of neurons and astrocytes. Many aspects of the structure and function of the Drosophila CNS and astrocytes are similar to humans. An aggregation-prone protein, associated with Spinocerebellar Ataxia 3 (SCA3polyQ78), was expressed in Drosophila eyes or neurons, resulting in a degenerative phenotype. A candidate screen was performed to identify genes in astrocytes that contributed to SCA3polyQ78-induced neurodegeneration. One of the identified genes in astrocytes was a conserved NF-kB gene, Relish. Relish inhibition in astrocytes delayed SCA3polyQ78-induced neurodegeneration. Similar observations were made in a Drosophila model for Alzheimer’s disease. We further studied the upstream modulation of activity of distinct NF-kB transcription factors, and found that this occurs via distinct isoforms of the calcineurin phosphatase. Calcineurin genes in astrocytes can also contribute to SCA3polyQ78-induced neurodegeneration. Thus, modulating the activity of specific calcineurin isoforms may be of relevance in regulating the activity of a specific NF-kB in NDs.Together, findings in this thesis demonstrate the relevance of astrocytes in NDs.

M3 - Thesis fully internal (DIV)

SN - 978-94-034-0765-4

PB - University of Groningen

CY - [Groningen]

ER -

The identification of cell non-autonomous roles of astrocytes in neurodegeneration

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