小柯机器人

美国洛克菲勒大学Nathaniel Heintz课题组揭示人类纹状体和小脑中突变型亨廷顿的细胞特异性CAG重复扩增和毒性。这一研究成果于2024年1月30日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，脑区特异性变性和突变型亨廷顿（mHTT）CAG束的体细胞扩增是亨廷顿氏病（HD）的主要特征。然而，CAG扩增、特定细胞类型的死亡以及与这些过程相关的分子事件之间的关系尚未确定。

研究人员利用荧光激活核分选（FANS）和深度分子剖析，深入了解了人类纹状体和小脑细胞类型在HD和对照供体中的特性。纹状体中刺神经元（MSN）、胆碱能中间神经元和小脑浦肯野神经元的mHTT出现了CAG扩增，SCA3供体的MSN出现了突变ATXN3。MSN中的CAG扩增与较高水平的MSH2和MSH3（形成MutSβ）有关，而MSH2和MSH3可抑制FAN1对CAG滑出的核裂解切除。这些数据支持一个模型，即：CAG扩增对细胞死亡是必要的，但可能还不够，并确定了与体细胞CAG扩增和纹状体毒性相关的转录变化。

附：英文原文

Title: Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Author: Mtlik, Kert, Baffuto, Matthew, Kus, Laura, Deshmukh, Amit Laxmikant, Davis, David A., Paul, Matthew R., Carroll, Thomas S., Caron, Marie-Christine, Masson, Jean-Yves, Pearson, Christopher E., Heintz, Nathaniel

Issue&Volume: 2024-01-30

Abstract: Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.

DOI: 10.1038/s41588-024-01653-6

Source: https://www.nature.com/articles/s41588-024-01653-6

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