Amplification of neurotoxic HTTex1 assemblies in human neurons.
Amplification of neurotoxic HTTex1 assemblies in human neurons.
复制标题
DOI：
10.1016/j.nbd.2021.105517
复制
发表时间：
2021-11
影响因子：
6.1
通讯作者：
Khoshnan A
中科院分区：
文献类型：
--
作者：
Chongtham A;Isas JM;Pandey NK;Rawat A;Yoo JH;Mastro T;Kennedy MB;Langen R;Khoshnan A
亨廷顿病（HD）是由亨廷顿蛋白（HTT）外显子1中的多聚谷氨酰胺（polyQ）重复扩增引起的遗传性神经退行性疾病。扩展的polyQ增强了HTT外显子1（HTTex 1）的淀粉样蛋白生成倾向，这形成了具有广泛神经毒性谱的组装体的异质混合物。虽然主要是细胞内，单体和聚集的突变HTT种类也存在于HD患者的脑脊液中，但是，它们的生物学特性还不清楚。为了探索细胞外突变体HTT在聚集和毒性中的作用，我们研究了重组HTTex 1组装体在细胞培养模型中的摄取和扩增。我们发现，小HTTex 1纤维优先进入人类神经元，并触发神经毒性组件的放大;星形胶质细胞或上皮细胞是不允许的。HTTex 1在神经元中的扩增消耗具有非致病性polyQ重复序列的内源性HTT蛋白，激活凋亡caspase-3通路并诱导核碎裂。使用一组新的单克隆抗体和基因突变，我们确定了HTTex 1的N-末端17个氨基酸和富含脯氨酸的结构域内的表位在神经摄取和扩增中至关重要。来自HD小鼠脑匀浆的突触体制剂也含有突变HTT种类，其进入神经元并表现出类似于小的重组HTTex 1原纤维。这些研究表明，淀粉样蛋白的细胞外突变HTTex 1组件可能优先进入神经元，传播和促进神经变性。
Huntington’s disease (HD) is a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeat in the exon-1 of huntingtin protein (HTT). The expanded polyQ enhances the amyloidogenic propensity of HTT exon 1 (HTTex1), which forms a heterogeneous mixture of assemblies with a broad neurotoxicity spectrum. While predominantly intracellular, monomeric and aggregated mutant HTT species are also present in the cerebrospinal fluids of HD patients, however, their biological properties are not well understood. To explore the role of extracellular mutant HTT in aggregation and toxicity, we investigated the uptake and amplification of recombinant HTTex1 assemblies in cell culture models. We find that small HTTex1 fibrils preferentially enter human neurons and trigger the amplification of neurotoxic assemblies; astrocytes or epithelial cells are not permissive. The amplification of HTTex1 in neurons depletes endogenous HTT protein with non-pathogenic polyQ repeat, activates apoptotic caspase-3 pathway and induces nuclear fragmentation. Using a panel of novel monoclonal antibodies and genetic mutation, we identified epitopes within the N-terminal 17 amino acids and proline-rich domain of HTTex1 to be critical in neural uptake and amplification. Synaptosome preparations from the brain homogenates of HD mice also contain mutant HTT species, which enter neurons and behave similar to small recombinant HTTex1 fibrils. These studies suggest that amyloidogenic extracellular mutant HTTex1 assemblies may preferentially enter neurons, propagate and promote neurodegeneration.
登录
查看更多内容
影响因子：
4.8
作者：
Bugg, Charles W.;Isas, J. Mario;Langen, Ralf
通讯作者：
Langen, Ralf
影响因子：
--
作者：
Ghosh, Rhia;Tabrizi, Sarah J
通讯作者：
Tabrizi, Sarah J
影响因子：
3.5
作者：
Maiuri, Tamara;Mocle, Andrew J.;Truant, Ray
通讯作者：
Truant, Ray
影响因子：
4.6
作者：
Askeland G;Dosoudilova Z;Rodinova M;Klempir J;Liskova I;Kuśnierczyk A;Bjørås M;Nesse G;Klungland A;Hansikova H;Eide L
通讯作者：
Eide L
影响因子：
25
作者：
Jucker M;Walker LC
通讯作者：
Walker LC