Use of an Atg16l1 mouse model to study the role played by autophagy in neuroprotection

Bicsak, Bertalan (2015) Use of an Atg16l1 mouse model to study the role played by autophagy in neuroprotection. Doctoral thesis, University of East Anglia.

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Abstract

Atg16l1 is an autophagy protein, most known for its association with Crohn’s disease. While knockout models of autophagy pathway components recapitulated neurodegeneration in laboratory mouse, the effect of Atg16l1 KO on neuronal protein homeostasis has been unknown. This study found Atg16l1 KO lethal on the first postnatal day, in the absence of gross deformity; as neonates fail to commence suckling. Histopathological analysis revealed the accumulation of detergent in soluble aggregates of polyubiquitinated proteins in their central nervous system and in various other tissues. While polyubiquitinated aggregates are commonly associated with human neurodegenerative diseases, cell damage or accumulation of pathogenic proteins was not observed.
To investigate autophagy in the context of virus‐host interaction, Semliki Forest Virus infection was tested in Atg16l1 KO tissues. Atg16l1 KO had no effect on virus proliferation in organotypic brain slice cultures while viral nsP1 and capsid expression was reduced in Atg16l1 KO embryonic fibroblast cultures. Semliki Forest Virus markers did not colocalize with autophagosomes in autophagy competent cells. While Semliki Forest Virus causes widespread encephalitis in vivo, virus replication is limited ex vivo in organotypic brain slice cultures.

Autophagy induction by diet is of great medical interest as epidemiological data suggest a protective effect against neurodegenerative diseases of the elderly. An important aim of this study was to determine the autophagy induction threshold of polyphenols concentrated in red wine. Resveratrol and quercetin induced autophagy in a non‐canonical manner at or above 10 uM in tissue cultures. These results underpin the feasibility of pharmacological but not the dietary administration of polyphenols for therapeutic purposes.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Stacey Armes
Date Deposited:	26 Jan 2016 15:14
Last Modified:	26 Jan 2016 15:14
URI:	https://ueaeprints.uea.ac.uk/id/eprint/56778
DOI:

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