Aberrantly folded proteins and neurodegeneration Protein aggregation diseases, such as Parkinson's disease (PD), are associated with accumulation of aggregated misfolded proteins. While we know that the aberrant protein structures are involved in cell dysfunction and pathology, their specific cellular mechanisms are not well understood. Health © Thinkstock Aggregation-prone proteins, or APPs, have different structures and properties; however, the structural features of the mature aggregates are strongly conserved. Recent data identified over 100 genetic modulators that can significantly reduce or enhance toxicity of each APP. While these modulators have high potential for therapeutic purposes, their mechanisms of action are still unknown. The project 'Understanding the cytotoxicity of aberrantly folded proteins in neurodegeneration' (FOLDTOX) applied integrated system-level analysis to models of protein aggregation. The goal was to identify responses activated upon formation of intracellular protein aggregates, and to understand how cells counteract the proteotoxic insult. FOLDTOX data revealed that the majority of cell responses depended on the sequence of the aggregating protein. This result suggests that the toxicity mechanisms of APPs are not generic. Among the responses activated by cells in response to aggregate accumulation were those involved in neuronal protein degradation. The project developed a novel screening method based on sentinel proteins — i.e. protein markers reporting activation of a given cellular pathway. A targeted proteomics assay constructed during the project measured about 200 sentinels in 1 hour, reporting about 300 functional modules. This high-throughput method may help find strategies to address protein aggregation diseases. FOLDTOX also developed a novel structural approach to quantify and characterise different conformational states of a protein directly in its cellular environment. The approach resulted in the identification of peptide markers specific for the detection of the pathological and 'healthy' forms of alpha-Syn in a variety of patient specimens. Scientists demonstrated that ubiquitin-mediated degradation selectively targets the toxic form of alpha-Syn, protecting cells from cytotoxicity. The discovery of a novel cellular mechanism of clearance of pathological protein aggregates in PD can lead to the development of novel therapeutic strategies designed to inhibit PD progression across neurons. Keywords Aberrantly folded proteins, neurodegeneration, protein aggregation, Parkinson's disease, cytotoxicity
