The Convergence of Titin and Elongator in Amyotrophic Lateral Sclerosis

点击翻译按钮获取中文摘要

Project Summary Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that ravages motor neurons and the voluntary muscles they innervate, is the most common motor neuron disease. Nucleolar stress was recently identified as an underlying pathogenic mechanism in ALS, common to both familial and sporadic forms, that triggers the degeneration of motor neurons. This proposal describes the discovery that titin, the largest protein in the human proteome, is present in the nucleolus of motor neurons and seeks to demonstrate that its function in this organelle and its regulation by the Elongator complex converge on the nucleolus as a nexus of disease pathogenesis in ALS. The proposal includes three Aims. In the first aim, titin’s presence in neurons will be fully characterized including identification of the specific central and peripheral nervous system cell types that exhibit nucleolar. The second aim will test the hypothesis that titin, encoded by TTN, is required for motor neuron homeostasis and that titin dysfunction represents a novel underlying pathogenic mechanism in ALS. The use of a conditional knockout mouse where TTN is selectively ablated in motor neurons will serve as a powerful approach for investigating this hypothesis. The third aim seeks to understand why mutations in the Elongator complex are associated with ALS and posits that Elongator may actually regulate the production of titin as a common underlying mechanism of disease. Mice in which the Elongator protein 1 (Elp1) is selectively ablated in motor neurons exhibit severely compromised motor function, demonstrating that the loss of Elp1 is sufficient to arrive at an ALS phenotype. These mice again provide a powerful tool for investigating Elongator targets whose misregulation contribute to ALS. Accomplishment of the described specific aims will significantly advance our understanding of the underlying molecular and cellular pathways that go awry to precipitate the onset and progression of ALS and will identify new targets for the development of effective therapeutics to treat the disease.