中央研究院院士
美國國家醫學院院士

The formation and maintenance of long lasting memories require specific gene expression programs that are in part, regulated by epigenetic mechanisms. Profound alteration in gene expression in the brain, which are likely to be mediated by epige netic mecha nisms, has been observed in the brains of human memory disorders, including cognitive aging and Alzheimer's disease (AD). Histone acetylation is a prominent epigenetic modification that has been unequivocally associated with increasing the rate of gene transcription. Histone deacetylase 2 (HDAC2) is an important chromatin enzyme that negatively regulates the expression of genes essential for synaptic plasticity and memory formation. Levels of HDAC2 are markedly upregulated in aged mouse brain, in the brain of several mouse models of AD, as well as in human postmortem AD brain. Elevation of HDAC2 can be directly induced by neurotoxic insults such as -amyloid peptides and oxidative stress. Increases in HDAC2, in turn, lead to a blockade of the expression of genes necessary for synaptic plasticity, and the eventual constraint of cognitive abilities. Reversing the build-up of HDAC2 unlocks the epigenetic blockade of gene expression and abolishes neurodegeneration-associated memory impairments in mouse models of AD. These results highlight the role of epigenetic mechanisms that mediate gene expression in the pathophysiology of memory disorders, and hint at the potential of targeting these mechanisms for therapeutic intervention.

長期記憶的形成和維持都需要特定基因的表現，而表觀遺傳 (epigenetic)的調控機制為參與此特定程式之重要步驟。表觀遺傳調控所造成的大腦基因表現改變,也可能是造成認知老化 (cognitive aging) 和阿茲海默症（AD）之記憶障礙的原因。組蛋白乙醯化 (Histone acetylation)是一種表觀遺傳變異，會伴隨著基因轉錄的增加。而組蛋白去乙醯酶2（HDAC2）是一種重要的染色質酵素，它抑制神經突觸可塑性(synaptic plasticity)和記憶形成所需的基因表現。在年老的小鼠，患有AD的小鼠以及AD病人的大腦中，細胞HDAC2的表現量都有顯著的增加。神經毒素如乙型類澱粉胜肽 (-amyloid peptides) 或氧化壓力會直接導致HDAC2蛋白質明顯增加，進而減低突觸可塑性相關的基因表現，最後造成認知功能障礙。若將這些異常增加的HDAC2壓制回正常量，則可以解除被封鎖的表觀遺傳，並緩解AD小鼠的神經退化與記憶障礙。這些結果顯示，表觀遺傳機制所調控的基因表現，對記憶相關疾病的病理影響重大，並且暗示了此機制作為未來治療標靶的可能性。

Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease. Yet, the mechanisms that protect neurons from genotoxic stress remain largely obscure. We previously reported the identification of DNA double stranded breaks (DSBs) in the hippocampal neurons of mice in the pre-symptomatic CK-p25 mouse model of neurodegeneration. Activation of the histone deacetylase, HDAC1, and the sirtuin, SIRT1, by either viral mediated overexpression or small molecule activators treatment ameliorated DSBs and cell loss, indicating important neuroprotective roles for HDAC1 and SIRT1. Using a combination of mouse genetics and biochemical approaches, we show that HDAC1 and SIRT1 are part of the DNA damage repair machinery necessary for promoting repair through the nonhomologous end-joining pathway (NHEJ). Importantly, SIRT1 deacetylates HDAC1 and stimulates its enzymatic activity, which is necessary for DNA repair through the NHEJ pathway. These results suggest that the two deacetylases, SIRT1 and HDAC1, collaborate to promote genomic integrity. Recently, we have detected DSBs in two additional models of neurodegeneration, including the tau P301S, and FUSR521C transgenic mice. FUS is a familial amyotrophic lateral sclerosis (ALS) gene. We found that FUS is an integral player of the DNA damage response pathway and that its interaction with HDAC1 is necessary to mediate DNA repair. Based on these findings, we propose that DNA damage plays a prominent role in contributing to neurodegeneration, with impaired genome integrity rendering neurons more vulnerable to insults caused by other risk factors, and eventually culminating in neurodegenerative disease.

認知能力會隨著年長或神經退化性疾病而下降, 這個過程和DNA缺陷的修復有重要的關聯。然而，神經細胞如何自我防禦避免被基因毒性的侵襲至今仍隱晦不明。我們實驗室曾經報導，患有CK-p25神經退化性疾病的小鼠，病發前其大腦海馬迴的神經元有DNA雙股斷裂的現象。利用病毒感染或以小分子化合物來活化histone deacetylase （HDAC1）和sirtuin (SIRT1) 去乙醯酶，可以阻斷DNA的雙股斷裂與細胞凋零，顯示HDAC1和SIRT可以保護神經。我們進一步結合小鼠遺傳和生化的技術，證明HDAC1和SIRT1會參與DNA修復機制，並過非同源末端連接途徑（NHEJ）來修復受損的DNA。SIRT1可以去除HADC1的乙醯，促進HDAC1的活性，從而修復DNA。上述結果顯示SIRT1和HDAC1這兩個去乙醯酶一起增進基因組的完整性。最近，我們檢測到tau P301S與FUSR521C兩種基因轉殖小鼠, 也因DNA之雙股斷裂而神經退化。FUS基因突變引起家族性肌萎縮側索硬化症（ALS）。我們發現FUS蛋白也會透過HDAC1來調控 DNA的損傷修復。基於這些發現，我們認為DNA的損傷會導致神經退化，由於基因組的受損使神經元更容易被其他危險因子侵襲，最終導致神經退化性疾病。