title: Mutation in E1, the ubiquitin activating enzyme, reduces Drosophila lifespan and results in motor impairment.
abstract: Neurodegenerative diseases cause tremendous suffering for those afflicted and their families. Many of these diseases involve accumulation of mis-folded or aggregated proteins thought to play a causal role in disease pathology. Ubiquitinated proteins are often found in these protein aggregates, and the aggregates themselves have been shown to inhibit the activity of the proteasome. These and other alterations in the Ubiquitin Pathway observed in neurodegenerative diseases have led to the question of whether impairment of the Ubiquitin Pathway on its own can increase mortality or if ongoing neurodegeneration alters Ubiquitin Pathway function as a side-effect. To address the role of the Ubiquitin Pathway in vivo, we studied loss-of-function mutations in the Drosophila Ubiquitin Activating Enzyme, Uba1 or E1, the most upstream enzyme in the Ubiquitin Pathway. Loss of only one functional copy of E1 caused a significant reduction in adult lifespan. Rare homozygous hypomorphic E1 mutants reached adulthood. These mutants exhibited further reduced lifespan and showed inappropriate Ras activation in the brain. Removing just one functional copy of Ras restored the lifespan of heterozygous E1 mutants to that of wild-type flies and increased the survival of homozygous E1 mutants. E1 homozygous mutants also showed severe motor impairment. Our findings suggest that processes that impair the Ubiquitin Pathway are sufficient to cause early mortality. Reduced lifespan and motor impairment are seen in the human disease X-linked Infantile Spinal Muscular Atrophy, which is associated with mutation in human E1 warranting further analysis of these mutants as a potential animal model for study of this disease.
authors: Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Hsiu-Yu
authors: HY
authors: Liu
authors: Cathie M
authors: CM
authors: Pfleger
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008136:Longevity / Q000235:genetics / Q000502:physiology; D009043:Motor Activity / Q000235:genetics / Q000528:radiation effects; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000502:physiology; D017510:Protein Folding; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics* / Q000503:physiopathology; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D046988:Proteasome Endopeptidase Complex; C542423:Uba1 protein, Drosophila; D044764:Ubiquitin-Activating Enzymes
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