An Elongator Knock Out Mouse Model for ALS

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that results in the death of motor neurons. As a consequence of motor neuron death, the muscles they innervate atrophy, causing patients to lose their ability to walk, talk, eat, and eventually breath, such that patients typically die within 4 years of diagnosis. Worldwide, ALS is the most common motor neuron disease. Fifteen people are diagnosed with ALS every day and importantly, the number of cases is projected to increase 69% by the year 2040. The George Lab studies a molecular complex called Elongator, and specific mutations in genes encoding Elongator subunits are associated with ALS. To determine whether motor neurons express Elongator, we used a genetically engineered reporter mouse that “reports” the expression of Elp1, encoding the scaffolding subunit for Elongator. Our results indicate that Elp1 is in fact expressed by alpha motor neurons, a subpopulation of motor neurons in the spinal cord that is most impacted in ALS. To investigate Elongator’s specific function in this cell type, we then generated a conditional knockout (CKO) mouse, where Elp1 is selectively ablated in motor neurons. These mice exhibit reduced motor function, as evidenced by PaGE testing, motor fasciculations, diminished muscle mass and overall body weight (~ ½ the weight of their littermate controls), and a shortened life span (averaging only 3 months). All of these symptoms are hallmark features of ALS. We hypothesized that the phenotype of our CKO mice is due to the death of motor neurons. To investigate this question, the number of alpha motor neurons in the lumbar enlargement was quantified in control and CKO mice using immunohistochemistry and Image J software. Alpha motor neuron numbers were found to be significantly decreased in the CKO. In conclusion, these data demonstrate that Elongator function is essential for the function and survival of motor neurons. Additionally, our Chat-Cre; Elp1LoxP/LoxP mice represent a new Elongator mouse model for studying the cellular and molecular mechanisms that contribute to ALS.