Structural variant in mitochondrial-associated gene (MRPL3) induces adult-onset neurodegeneration with memory impairment in the mouse

• Published in: The Journal of neuroscience 2020-06, Vol.40 (23), p.4576-4585
• Main Authors: 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, Sled, John G
• Format: Article
• Language: English
• Subjects: Anatomy; Animal diseases; Animal models; Brain architecture; Cell death; Embryos; Energy metabolism; Impairment; In vivo methods and tests; Lethality; Limbic system; Magnetic resonance imaging; Mitochondria; Mutation; Neurodegeneration; Neurodegenerative diseases; Neuroimaging; Phenotypes; Precipitates
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0013-20.2020

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 magnetic resonance imaging and behavioural 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 ( ) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in knockout 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. 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.