We have identified two independent ENU-induced mouse mutations in the nuclear export mediating factor (Nemf) causing a motor neuron disease with many phenotypic hallmarks of amyotrophic lateral sclerosis (ALS). NEMF has recently been shown to be a key component of the stalled-ribosome quality control complex (RQC) that allows for ubiquitination, C-terminal addition of poly Ala/Thr tails (CAT-tails) and disposal of ribosome-stalled nascent polypeptide chains. Co-PI Joazeiro has previously characterized a mouse model of neurodegeneration caused by ENU mutation of another RQC complex member, Listerin (Ltn1). In several ways, the Ltn1-ENU phenotype resembles that of other mouse models of ALS including the newly discovered Nemf mouse models, thus solidifying the connection between RQC dysfunction and neurodegeneration. Preliminary work has identified human sporadic ALS patients with rare and potentially damaging NEMF polymorphisms. Thus, the identification of the novel NEMF mouse model provides a key resource for determining how defects in protein quality control mechanisms may lead to neurological disease. We hypothesize that misregulated ribosomal quality control can underlie motor neuron disease, and that NEMF is a putative new ALS-associated disease gene critical for regulating normal neuronal function. !
The goal of this basic research proposal is to characterize a novel enzymatic activity whose loss we have found to be associated with neurodegeneration in mice, and to determine to what extent this activity plays a protective role against human disease. By elucidating molecular mechanisms underlying neurodegenerative disorders, the proposed work is expected to open the way to the development of new therapeutic rationale and approaches.
|Joazeiro, Claudio A P (2017) Ribosomal Stalling During Translation: Providing Substrates for Ribosome-Associated Protein Quality Control. Annu Rev Cell Dev Biol 33:343-368|