Age-dependent processes and molecular pathways of the fungal ageing model "Podospora anserina": A bioinformatics approach

Biological ageing is a degenerative and irreversible process, ultimately leading to death of the organism. The process is complex and under the control of genetic, environmental and stochastic traits. Although many theor
Biological ageing is a degenerative and irreversible process, ultimately leading to death of the organism. The process is complex and under the control of genetic, environmental and stochastic traits. Although many theories have been established during the last decades, none of these are able to fully describe the complex mechanisms, which lead to ageing. Generally, biological processes and environmental factors lead to molecular damage and an accumulation of impaired cellular components. In contrast, counteracting surveillance systems are effective, including repair, remodelling and degradation of damaged or impaired components, respectively. Nevertheless, at some point these systems are no longer effective, either because the increasing amount of molecular damages can not longer be removed efficiently or because the repairing and removing mechanisms themselves become affected by impairing effects. The organism finally declines and dies. To investigate and to understand these counteracting mechanisms and the complex interplay of decline and maintenance, holistic and systems biological investigations are required. Hence, the processes which lead to ageing in the fungal model organism Podospora anserina, had been analysed using different advanced bioinformatics methods. In contrast to many other ageing models, P. anserina exhibits a short lifespan, a less biochemical complexity and it provides a good accessibility for genetic manipulations.
To achieve a general overview on the different biochemical processes, which are affected during ageing in P. anserina, an initial comprehensive investigation was applied, which aimed to reveal genes significantly regulated and expressed in an age-dependent manner. This investigation was based on an age-dependent transcriptome analysis. Sophisticated and comprehensive analyses revealed different age-related pathways and indicated that especially autophagy may play a crucial role during ageing. For example, it was found that the expression of autophagy-associated genes increases in the course of ageing.
Subsequently, to investigate and to characterise the autophagy pathway, its associated single components and their interactions, Path2PPI, a new bioinformatics approach, was developed. Path2PPI enables the prediction of protein-protein interaction networks of particular pathways by means of a homology comparison approach and was applied to construct the protein-protein interaction network of autophagy in P. anserina. 
The predicted network was extended by experimental data, comprising the transcriptome data as well as newly generated protein-protein interaction data achieved from a yeast two-hybrid analysis. Using different mathematical and statistical methods the topological properties of the constructed network had been compared with those of randomly generated networks to approve its biological significance. In addition, based on this topological and functional analysis, the most important proteins were determined and functional modules were identified, which correspond to the different sub-pathways of autophagy. Due to the integrated transcriptome data the autophagy network could be linked to the ageing process. For example, different proteins had been identified, which genes are continuously up- or down-regulated during ageing and it was shown for the first time that autophagy-associated genes are significantly often co-expressed during ageing.
The presented biological network provides a systems biological view on autophagy and enables further studies, which aim to analyse the relationship of autophagy and ageing. Furthermore, it allows the investigation of potential methods for intervention into the ageing process and to extend the healthy lifespan of P. anserina as well as of other eukaryotic organisms, in particular humans.
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Metadaten
Author:Oliver Philipp
URN:urn:nbn:de:hebis:30:3-450853
Place of publication:Frankfurt am Main
Referee:Ina Koch, Heinz D. Osiewacz
Document Type:Doctoral Thesis
Language:English
Date of Publication (online):2017/11/15
Year of first Publication:2017
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Granting Institution:Johann Wolfgang Goethe-Universität
Date of final exam:2017/11/14
Release Date:2017/11/23
Tag:Ageing; Autophagy; Podospora anserina; Protein-protein interaction; Transcriptome analysis
Pagenumber:XII, 130
HeBIS PPN:421468793
Institutes:Informatik und Mathematik
Dewey Decimal Classification:000 Informatik, Informationswissenschaft, allgemeine Werke
510 Mathematik
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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