Principal Investigators

    LAMITINA, SAMUEL T

    Institution

    UNIVERSITY OF PITTSBURGH AT PITTSBURGH

    Contact information of lead PI

    Country

    USA

    Title of project or programme

    Mechanisms of C9orf72-associated dipeptide toxicity

    Source of funding information

    NIH (NINDS)

    Total sum awarded (Euro)

    388532.1101

    Start date of award

    15/08/2015

    Total duration of award in years

    1

    Keywords

    C9orf72, Dipeptides, frontotemporal lobar dementia-amyotrophic lateral sclerosis, Toxic effect, Caenorhabditis elegans

    Research Abstract

    ? DESCRIPTION (provided by applicant): Hexanucleotide expansions in the C9orf72 gene cause ~50% of all familial ALS cases. The mechanism(s) by which this expansion causes disease are not known. Current hypotheses to explain the disease mechanism include haploinsufficiency and gain-of-function RNA and/or protein toxicity. Despite its presence in an intron, the disease causing expansion is translated into protein in multiple reading frames from both the sense and anti-sense strands to produce five distinct dipeptide proteins. Expression of each of these dipeptides has been specifically detected in ALS patient samples. Several recent studies, as well as our own data, show that the arginine dipeptides exhibit substantial neurotoxicity through unknown mechanisms. Here, we will use genetic screening in C. elegans, followed by validation in Drosophila and mammalian cells, to identify these mechanisms. Our studies will provide significant new insights into the pathways by which dipeptides engages and kill motor neurons and may identify novel risk factors and new therapeutic targets for treating this currently incurable disease

    Further information available at:

Types: Investments < €500k
Member States: United States of America
Diseases: N/A
Years: 2016
Database Categories: N/A
Database Tags: N/A

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