A30 Identification of MOAG-4/SERF as a regulator of age related proteotoxicity

Burggraaff, R; van Ham, T; Holmberg, M; van der Goot, A; Teuling, E; Garcia-Arencibia, M; Kim, H-E; Du, D; Thijssen, K; Wiersma, M; van Bergeijk, P; van Rheenen, J; van Veluw, J; Hofstra, R; Rubinsztein, D C; Nollen, E
September 2010
Journal of Neurology, Neurosurgery & Psychiatry;Sep2010 Supp, Vol. 81, pA10
Academic Journal
Background Fibrillar protein aggregates are the major pathological hallmark of several incurable, age related, neurodegenerative disorders. These aggregates typically contain aggregation prone pathogenic proteins, such as amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular ageing. Aims The aim of this study was to identify genes that regulate aggregation. Methods In order to investigate this we performed a chemical mutagenesis screen in a model for polyglutamine diseases. Results We have identified an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-β and α-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation and autophagy. Conclusions Our results suggest that MOAG-4/SERF regulates age related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age related, neurodegenerative diseases.


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