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.