Perez-Canamas Azucena, Takahashi Hideyuki, Lindborg Jane A, Strittmatter Stephen M
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA.
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
Brain Commun. 2020 Nov 16;3(1):fcaa200. doi: 10.1093/braincomms/fcaa200. eCollection 2021.
TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified as a risk modifier of Alzheimer's disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic -/- mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred mice with , a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues phenotypes. In contrast, gene-edited neuronal loss of causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.
跨膜蛋白106B（TMEM106B）是一种定位于内溶酶体区室的跨膜蛋白。全基因组关联研究已将其确定为阿尔茨海默病和额颞叶痴呆的风险修饰因子，尤其是在原颗粒蛋白单倍体不足的情况下。我们最近证明，TMEM106B的缺失可挽救原颗粒蛋白基因敲除小鼠的表型，包括溶酶体酶失调、神经退行性变和行为改变。然而，TMEM106B是否参与其他神经退行性溶酶体疾病尚不清楚。在这里，我们使用戈谢病和神经元蜡样脂褐质沉积症的原颗粒蛋白非依赖模型，评估TMEM106B在改变溶酶体贮积症进展中的潜在作用。为了研究戈谢病，我们在野生型和低表达-/-小鼠中采用了使用抑制剂环氧苦楝醇的药理学方法。TMEM106B的缺失改善了戈谢病药理学模型中的神经元变性和一些行为异常，类似于其对某些原颗粒蛋白基因敲除表型的影响。为了研究TMEM106B在神经元蜡样脂褐质沉积症中的作用，我们将小鼠与该疾病的遗传模型小鼠进行杂交。与其对环氧苦楝醇的挽救作用相反，TMEM106B的缺失加剧了小鼠浦肯野细胞变性和运动缺陷。从机制上讲，已知TMEM106B与液泡ATP酶的亚基相互作用并影响溶酶体酸化。在药理学戈谢病模型中，酸化的溶酶体区室增强，TMEM106B的缺失挽救了相关表型。相反，基因编辑导致的TMEM106B缺失会导致液泡ATP酶水平降低和酸化溶酶体区室受损，而TMEM106B的缺失会加剧小鼠的表型。我们的研究结果表明，TMEM106B对溶酶体贮积症戈谢病和神经元蜡样脂褐质沉积症的进展具有不同的调节作用。TMEM106B在神经退行性变中的作用因液泡ATP酶状态和溶酶体pH值的调节而异。这些数据表明TMEM106B可作为纠正溶酶体pH值改变的靶点，特别是用于戈谢病和神经元蜡样脂褐质沉积症的治疗干预。
