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’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.
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.
| Original language | English |
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| Qualification | Doctor of Philosophy |
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| Supervisors/Advisors |
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| Award date | 11-Jun-2018 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-94-034-0765-4 |
| Electronic ISBNs | 978-94-034-0766-1 |
| Publication status | Published - 2018 |