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    Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD

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    Author
    Wang, Shaoteng
    Tatman, Micaela
    Monteiro, Mervyn J
    Date
    2020-10-07
    Journal
    Acta neuropathologica communications
    Publisher
    Springer Nature
    Type
    Article
    Other
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1186/s40478-020-01039-9
    Abstract
    Missense mutations in UBQLN2 cause X-linked dominant inheritance of amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 belongs to a family of four highly homologous proteins expressed in humans that play diverse roles in maintaining proteostasis, but whether one isoform can substitute for another is not known. Here, we tested whether overexpression of UBQLN1 can alleviate disease in the P497S UBQLN2 mouse model of ALS/FTD by crossing transgenic (Tg) mouse lines expressing the two proteins and characterizing the resulting genotypes using a battery of pathologic and behavioral tests. The pathologic findings revealed UBQLN1 overexpression dramatically reduced the burden of UBQLN2 inclusions, neuronal loss and disturbances in proteostasis in double Tg mice compared to single P497S Tg mice. The beneficial effects of UBQLN1 overexpression were primarily confirmed by behavioral improvements seen in rotarod performance and grip strength in male, but not female mice. Paradoxically, although UBQLN1 overexpression reduced pathologic signatures of disease in P497S Tg mice, female mice had larger percentage of body weight loss than males, and this correlated with a corresponding lack of behavioral improvements in the females. These findings lead us to speculate that methods to upregulate UBQLN1 expression may reduce pathogenicity caused by UBQLN2 mutations, but may also lead to gender-specific outcomes that will have to be carefully weighed with the therapeutic benefits of UBQLN1 upregulation.
    Keyword
    Amyotrophic lateral sclerosis
    Motor neuron disease
    Proteostasis
    UBQLN1
    UBQLN2
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13939
    ae974a485f413a2113503eed53cd6c53
    10.1186/s40478-020-01039-9
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