Long-term memory deficits in Huntingtons disease are associated with reduced CBP histone acetylase activity
Long-term memory deficits in Huntingtons disease are associated with reduced CBP histone acetylase activity
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DOI：
10.1093/hmg/ddr552
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发表时间：
2012-03-15
影响因子：
3.5
通讯作者：
Gines, S.
中科院分区：
文献类型：
--
作者：
Giralt, A.;Puigdellivol, M.;Gines, S.
亨廷顿病 (HD) 是一种常染色体显性遗传性进行性神经退行性疾病，由亨廷顿 (htt) 基因编码区的 CAG/聚谷氨酰胺重复序列扩展引起。虽然 HD 通常被认为是一种运动障碍，但现在有大量证据表明，患者在运动障碍发作之前就出现了早期认知缺陷。在这里，我们证明了杂合 HD 敲入突变小鼠 (Hdh(Q7/Q111))（一种遗传精确的 HD 小鼠模型）中长期空间和识别记忆的早期损伤。认知缺陷与海马 CREB 结合蛋白 (CBP) 表达减少和组蛋白 H3 乙酰化水平降低有关。与 CBP 降低相一致，与野生型小鼠相比，Hdh(Q7/Q111) 小鼠海马中与记忆相关的 CREB/CBP 靶基因（如 c-fos、Arc 和 Nr4a2）的表达显着降低。最后，与 CBP 在 Hdh(Q7/Q111) 小鼠认知障碍中的作用一致，给予组蛋白脱乙酰酶抑制剂曲古抑菌素 A 可挽救 Hdh(Q7/Q111) 小鼠的识别记忆缺陷和选择性 CREB/CBP 靶基因的转录。这些发现证明了 CBP 在 HD 认知功能障碍中的重要作用，并建议使用组蛋白脱乙酰酶抑制剂作为治疗这种疾病记忆缺陷的新治疗策略。
Huntingtons disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene. Although HD is classically considered a motor disorder, there is now considerable evidence that early cognitive deficits appear in patients before the onset of motor disturbances. Here we demonstrate early impairment of long-term spatial and recognition memory in heterozygous HD knock-in mutant mice (Hdh(Q7/Q111)), a genetically accurate HD mouse model. Cognitive deficits are associated with reduced hippocampal expression of CREB-binding protein (CBP) and diminished levels of histone H3 acetylation. In agreement with reduced CBP, the expression of CREB/CBP target genes related to memory, such c-fos, Arc and Nr4a2, was significantly reduced in the hippocampus of Hdh(Q7/Q111) mice compared with wild-type mice. Finally, and consistent with a role of CBP in cognitive impairment in Hdh(Q7/Q111) mice, administration of the histone deacetylase inhibitor trichostatin A rescues recognition memory deficits and transcription of selective CREB/CBP target genes in Hdh(Q7/Q111) mice. These findings demonstrate an important role for CBP in cognitive dysfunction in HD and suggest the use of histone deacetylase inhibitors as a novel therapeutic strategy for the treatment of memory deficits in this disease.