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PDcontrol Report Summary

Project ID: 281622
Funded under: FP7-IDEAS-ERC
Country: Netherlands

Final Report Summary - PDCONTROL (Protein damage control: regulation of toxic protein aggregation in aging-associated neurodegenerative diseases)

The worldwide aging population will lead to a dramatic increase in the number of people with Alzheimer’s disease and other incurable age-related neurodegenerative diseases over the next few decades. By 2050 over 115 million are expected to suffer from these devastating diseases. The major pathological hallmark of these disorders is the accumulation of aggregation-prone disease proteins in aggregates in the brain. To understand the disease mechanisms and to identify targets for treatment, we aim to uncover the cellular pathways that regulate disease-protein toxicity and aggregation (proteotoxicity).

Opening up such new avenues was our identification of a modifier of aggregation, which we named MOAG-4, as a general regulator of age-related proteotoxicity in worm (C. elegans) models for neurodegenerative diseases. MOAG-4 and its human counterpart SERF act independently of classical pathways that degrade proteins or prevent their aggregation, but their molecular role remained to be determined. We hypothesized that MOAG-4/SERF represented a new regulatory pathway of age-related proteotoxicity in neurodegenerative diseases.

With this ERC starting grant, we established that MOAG-4/SERF can interact directly and transiently with disease proteins, without the need of any assisting factors, and alters their shape to accelerate their aggregation. This unprecedented mechanism explains why loss of MOAG-4/SERF suppresses aggregation and toxicity independently of other protective mechanisms.

Our identification of additional modifiers revealed other cellular mechanism involved in protein aggregation and toxicity. These include MOAG-2/LIR-3, which normally regulates transcription of small non-coding RNAs in the nucleus but in presence of aggregation-prone proteins moves to the cytosol where it turns into an aggregation and toxicity promoting factor. Such mechanism of aggregation-prone proteins inactivating cellular factors and using them to propagate their own aggregation and toxicity may contribute to the progressive decline of cellular homeostasis in aging and age-related diseases.

In this collaborative project, we developed high throughput screening tools and exploited the power of genetics in C.elegans to identify cellular mechanisms, genes, and compounds that regulate age-related proteotoxicity. We developed mouse models that will allow us to work out organismal functions and the therapeutic potential of SERF and SERF-like factors. Our results offer new starting points for research and for the development of therapeutic interventions in the early molecular events of aging-associated neurodegenerative diseases.

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