Among the costliest diseases to society, and with rising prevalence in an aging population, neurodegenerative diseases pose a public health challenge. However, there are few options available for their treatment, and without pathomechanisms being sufficiently elucidated, one's ability to generate a rationale for interventions is greatly limited. Our studies are expected to address this barrier by establishing new etiological factors and molecular mechanisms of mammalian neurodegeneration. One such mechanism is Ribosome-associated Quality Control (RQC), that mediates the degradation of incomplete polypeptides produced by ribosomes that stall during translation. Key factors working in RQC are the Ltn1/Listerin E3 ubiquitin ligase and its partner, NEMF (Rqc2 in yeast). PI Joazeiro has previously found that Ltn1 mutation causes neurodegeneration in mice. PI Cox has more recently identified two independent mutations in mouse Nemf causing motor neuron disease and used this to knowledge to identify previously undiagnosed patients with a similar neuromuscular condition that inherited causative mutations in the human NEMF gene. In several ways, Ltn1-ENU and Nemf-ENU mice phenocopy each other, thus strengthening the connection between RQC dysfunction and neurodegeneration. The proposed studies are aimed at understanding molecular mechanisms underlying neurodegeneration caused by NEMF loss of function. We focus our analyses on a recently-discovered activity of NEMF that is conserved from bacteria to humans–the modification of aberrant nascent chains with C-terminal Alanine tails that have a proteolytic function. Based on our preliminary data, we hypothesize that NEMF-mediated Ala tailing protects neurons against degeneration. Results of these studies are expected to provide critical understanding of how defects in protein quality control lead to neurological disease.