Principal Investigators

    Institution

    Contact information of lead PI

    Country

    European Commission

    Title of project or programme

    C9orf72-mediated neurodegeneration: mechanisms and therapeutics

    Source of funding information

    European Commission Horizon 2020

    Total sum awarded (Euro)

    € 1,985,699

    Start date of award

    01/10/2015

    Total duration of award in years

    5.0

    The project/programme is most relevant to:

    Neurodegenerative disease in general

    Keywords

    Research Abstract

    An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat RNA is transcribed and accumulates in neuronal RNA aggregates, implicating RNA toxicity as a key pathogenic mechanism. However, the pathways that lead to neurodegeneration are unknown. My lab has made pioneering contributions to the understanding of C9orf72 FTD/ALS, and reported the first structure of the repeat RNA, and the first description of both sense and antisense RNA aggregates in patient brain. We have now developed new disease models that allow, for the first time, the dissection of RNA toxicity both in vivo and in sophisticated neuronal culture models. We have also used our knowledge of the repeat structure to identify novel small molecules that show very strong binding to the repeats. We will utilise our innovative disease models in a multidisciplinary approach to fully dissect the cellular pathways underlying C9orf72 repeat RNA toxicity in vivo, on a genome-wide scale. Altered RNA metabolism has been implicated in a wide range of neurodegenerative diseases, indicating that our findings will provide profound new insight into fundamental mechanisms of neuronal maintenance and survival. This research programme will also deliver a step change in our understanding of C9orf72 FTD/ALS pathogenesis and provide essential insight for the identification of small molecules with genuine therapeutic potential. RNA-mediated mechanisms are now known to be a common theme in neurodegeneration, suggesting these findings will have broad significance.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: European Commission
Diseases: Neurodegenerative disease in general
Years: 2016
Database Categories: N/A
Database Tags: N/A

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