Murru, Sara (2018). The role of astrocytes in neurological phenotypes associated with deficiency of the m-AAA protease. PhD thesis, Universität zu Köln.

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Abstract

Ongoing research is unveiling the role of glial cells in the development of neurological diseases. However, it is yet unclear whether mitochondrial dysfunction or altered mitochondrial dynamics can trigger astrocytic death or secondarily affect neuronal function. The mitochondrial m- AAA protease is essential for neuronal survival. Mutations in its subunits AFG3L2 and paraplegin lead to the development of different neurodegenerative diseases, spinocerebellar ataxia 28 (SCA28) and hereditary spastic paraplegia (HSP) respectively, which strongly affect patients’ motility. Glutamate excitotoxicity may be a contributor to the neurodegeneration, and increasing glutamate uptake by astrocytes ameliorates the phenotype caused by m-AAA protease dysfunction in a Afg3l2-deficient mouse model of SCA28. In order to dissect the contribution of astrocytes to the development of the neuronal death, I used two different murine models of m-AAA dysfunction. In my thesis, I show that deletion of Afg3l2 in astrocytes (astro-L2 KO) leads to the demise of the highly targeted Bergmann glia, radial cells in the cerebellar cortex, accompanied with a mild, late-onset motor impairment. When I ablated the m-AAA protease in astrocytes by eliminating both Afg3l2 and its murine-expressed homologue Afg3l1 (astro- DKO), the animals show a very strong and early-onset ataxic phenotype, characterized by induction of mitochondrial stress response, Bergmann glia loss, reactive astrogliosis and inflammation. EAAT1 and EAAT2 glutamate transporters are strongly reduced in cerebella of astro- DKO, and glutamate levels are also reduced. Furthermore, necroptotic markers are upregulated and Purkinje neurons, the biggest neurons in the cerebellum that are strongly affected in SCA28, show morphological and electrophysiological alterations, revealing a secondary neuronal dysfunction. I propose that the m-AAA protease dysfunction in astrocytes leads to glutamate excitotoxicity and inflammation that worsen the already dysfunctional neurons in patients carrying mutations in AFG3L2.

Item Type: Thesis (PhD thesis)
Creators:
CreatorsEmailORCID
Murru, Sarasmurru@smail.uni-koeln.deUNSPECIFIED
URN: urn:nbn:de:hbz:38-95179
Subjects: Natural sciences and mathematics
Life sciences
Uncontrolled Keywords:
KeywordsLanguage
TesiItalian
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Institute for Genetics
Language: English
Date: 1 October 2018
Date of oral exam: 19 November 2018
Referee:
NameAcademic Title
Rugarli, E.IProf. Dr.
Bergami, MatteoProf. Dr
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/9517

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