A novel strategy to control protein misfolding diseases and aging: Molecular mechanisms of transcellular chaperone signalling

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An increasing number of individuals in our aging population is faced with the devastatingconsequences of cumulative protein misfolding, one of the hallmarks leading to Alzheimer's orParkinson's Disease or ALS. In a multicellular setting, protein misfolding diseases use mechanisms topromote and spread the disease across different tissues and organs. Recent findings haveestablished that within the context of an entire organism, protective cellular mechanisms are at placethat allow to communicate stress and disease conditions across different tissues. For example, usingC. elegans as a model system, we have shown that mild stress induced in one tissue leads to a cytoprotectivechaperone response in multiple different tissues, known as Transcellular ChaperoneSignalling (Cell. 2013; 153(6): 1366-78). This results in increased stress resistance, extends lifespanand protects from protein misfolding in different cell types. Although transcellular chaperone signallingis conserved, the key players and the molecular mechanism of this inter-tissue signalling remainelusive thus far. Using genetic screens and transcriptome analysis, we have identified novelcomponents of the proteostasis network that play an instructive role in the activation of protectivestress responses across and between different tissues.In this project we will focus on these newly identified components, that comprise of secreted peptidesinvolved in the immune response and a transcription factor that belongs to the conserved BTB-ZFfamily. We will determine how they signal and activate protective responses in different tissues of C.elegans. We will investigate how the BTB-ZF transcription factor is involved in the regulation ofproteostasis and which protective gene programmes are initiated during stress, disease and aging,using tissue-specific chromatin profiling (ChIP-Seq) techniques in C. elegans.Finally, we will determine how the newly identified components can be used for the development ofnovel therapeutic interventions against human protein misfolding diseases. In particular we willelucidate which of the novel components have the capacity to delay protein aggregation using C.elegans models of human protein misfolding diseases, including Alzheimer's Disease andHuntington's Disease.