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dc.contributor.authorWang, Shaoteng
dc.contributor.authorTatman, Micaela
dc.contributor.authorMonteiro, Mervyn J
dc.date.accessioned2020-10-26T18:33:44Z
dc.date.available2020-10-26T18:33:44Z
dc.date.issued2020-10-07
dc.identifier.urihttp://hdl.handle.net/10713/13939
dc.description.abstractMissense 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.en_US
dc.description.urihttps://doi.org/10.1186/s40478-020-01039-9en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofActa neuropathologica communicationsen_US
dc.subjectAmyotrophic lateral sclerosisen_US
dc.subjectMotor neuron diseaseen_US
dc.subjectProteostasisen_US
dc.subjectUBQLN1en_US
dc.subjectUBQLN2en_US
dc.titleOverexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTDen_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.doi10.1186/s40478-020-01039-9
dc.identifier.pmid33028421
dc.source.volume8
dc.source.issue1
dc.source.beginpage164
dc.source.endpage
dc.source.countryUnited States
dc.source.countryEngland


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