Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.
Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.
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作者：
Wang W;Cao Q;Tan T;Yang F;Williams JB;Yan Z
表观遗传异常涉及与认知缺陷相关的神经退行性疾病，例如阿尔茨海默病（AD）。AD的一个共同特征是由过度磷酸化的tau组成的神经元缠结的积累。表达突变型P301 S人tau蛋白的转基因小鼠发生AD样进行性tau病理学和认知障碍。在这里，我们发现常染色质组蛋白赖氨酸N-甲基转移酶2（EHMT 2）在P301 S Tau小鼠（5-7个月大）的前额叶皮层（PFC）中显著升高，导致抑制性组蛋白标记H3 K9 me 2增加，这可以通过选择性EHMT抑制剂UNC 0642治疗逆转。行为测定显示，UNC 0642处理诱导P301 S Tau小鼠中空间和识别记忆缺陷的稳健拯救。同时，P301 S Tau小鼠中PFC神经元兴奋性和突触能突触传递的降低也通过UNC 0642处理正常化。此外，EHMT抑制显著减弱P301 S Tau小鼠PFC中过度磷酸化的tau水平。转录组学分析显示，P301 S Tau小鼠的UNC 0642治疗使PFC中的许多失调基因正常化，这些基因在细胞骨架和细胞外基质组织、离子通道和转运蛋白、受体信号传导和应激反应中富集。总之，这些数据表明，靶向组蛋白甲基化酶以调节基因表达可用于治疗与tau蛋白病相关的神经退行性疾病中的认知和突触缺陷。在阿尔茨海默病的前额叶皮质神经元中，EHMT和H3 K9 me 2水平升高，过度磷酸化的tau引起微管（MT）解体，导致突触强度降低和认知障碍（上图）。在用EHMT抑制剂UNC 0642治疗后，H3 K9 me 2水平正常化，tau磷酸化减少，MT稳定，导致突触强度增强和认知改善（下图）。
Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies. In prefrontal cortical neurons of Alzheimer's disease, EHMT and H3K9me2 levels are elevated, hyperphosphorylated tau causes microtubule (MT) disintegration, leading to reduced synaptic strength and cognitive impairment (top panel). After treatment with the EHMT inhibitor UNC0642, H3K9me2 level is normalized, tau phosphorylation is diminished, and MT is stabilized, leading to enhanced synaptic strength and cognitive improvement (bottom panel).
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影响因子：
13.6
作者：
Cao Q;Wang W;Williams JB;Yang F;Wang ZJ;Yan Z
通讯作者：
Yan Z
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
5.3
作者：
Bradley-Whitman, M. A.;Lovell, M. A.
通讯作者：
Lovell, M. A.
影响因子：
25
作者：
Nativio R;Donahue G;Berson A;Lan Y;Amlie-Wolf A;Tuzer F;Toledo JB;Gosai SJ;Gregory BD;Torres C;Trojanowski JQ;Wang LS;Johnson FB;Bonini NM;Berger SL
通讯作者：
Berger SL
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K