Structural Variant in Mitochondrial-Associated Gene (MRPL3) Induces Adult-Onset Neurodegeneration with Memory Impairment in the Mouse.
JMG;Age Factors, Animals, Female, Genetic Variation, Male, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondrial Proteins, Neurodegenerative Diseases, Ribosomal Proteins
J Neurosci 2020 Jun 3; 40(23):4576-4585
An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioral testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene (Mrpl3) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knock-out mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease.SIGNIFICANCE STATEMENT The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease.
Cahill, Lindsay S; Cameron, Jessie M; Winterburn, Julie; Macos, Patrick; Hoggarth, Johnathan; Dzamba, Misko; Brudno, Michael; Nutter, Lauryl M J; Sproule, Thomas J.; Burgess, Robert W.; Henkelman, R Mark; and Sled, John G, "Structural Variant in Mitochondrial-Associated Gene (MRPL3) Induces Adult-Onset Neurodegeneration with Memory Impairment in the Mouse." (2020). Faculty Research 2020. 272.