Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8(mnd) mice.
Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8(mnd) mice.
复制标题
DOI：
10.1186/s13023-022-02564-7
复制
发表时间：
2022-11-11
影响因子：
3.7
通讯作者：
Weimer, Jill M.
中科院分区：
文献类型：
--
作者：
Holmes, Andrew D.;White, Katherine A.;Pratt, Melissa A.;Johnson, Tyler B.;Likhite, Shibi;Meyer, Kathrin;Weimer, Jill M.
关键词：
CLN 8-Batten病（CLN 8病）是一种罕见的神经退行性疾病，其表型特征为运动和认知能力的进行性恶化、视觉症状、癫痫发作和过早死亡。CLN 8中的突变导致特征性巴滕病症状和全脑病理学，包括溶酶体储存物质的积累、神经胶质增生和神经变性。最近对Batten病其他亚型（CLN 1，CLN 3，CLN 6）的研究强调了生物性别对疾病和治疗结果的影响;然而，对CLN 8亚型的性别差异知之甚少。为了确定性别对CLN 8疾病负担和进展的影响，我们利用Cln 8 mnd小鼠模型来测量性别之间的组织病理学和行为结果的影响和进展。在脑病理学表现中观察到几个显著的性别差异，包括与Cln 8 mnd雄性小鼠相比，Cln 8 mnd雌性小鼠在躯体感觉皮质、丘脑腹后内侧/腹后外侧核、纹状体和海马中始终表现出更大的GFAP+星形胶质细胞增多和CD 68+小胶质细胞增生。此外，运动行为评估中的性别差异显示，Cln 8 mnd雌性小鼠的运动表现比雄性小鼠差，死亡更早。还检查了用AAV 9介导的基因疗法治疗的Cln 8 mnd小鼠以评估治疗结果的性别差异，其显示当对疗法作出响应时，性别之间没有明显差异。综上所述，我们的研究结果提供了生物性别作为Batten病进展和结局的修饰因子的进一步证据，从而在进行调查和监测治疗影响时无需考虑。在线版本包含补充材料，可通过10.1186/s13023-022-02564-7获得。
CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. Several notable sex differences were observed in the presentation of brain pathology, including Cln8mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact. The online version contains supplementary material available at 10.1186/s13023-022-02564-7.
登录
查看更多内容
影响因子：
3.5
作者：
Badura-Stronka M;Winczewska-Wiktor A;Pietrzak A;Hirschfeld AS;Zemojtel T;Wołyńska K;Bednarek-Rajewska K;Seget-Dubaniewicz M;Matheisel A;Latos-Bielenska A;Steinborn B
通讯作者：
Steinborn B
影响因子：
9.3
作者：
Han J;Fan Y;Zhou K;Blomgren K;Harris RA
通讯作者：
Harris RA
影响因子：
3.4
作者：
Gardner E;Mole SE
通讯作者：
Mole SE
影响因子：
6.4
作者：
Herva, R;Tyynelä, J;Haltia, M
通讯作者：
Haltia, M
影响因子：
4
作者：
HIRVASNIEMI, A;LANG, H;LEISTI, J
通讯作者：
LEISTI, J