The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS
The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS
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DOI：
10.1093/hmg/ddr326
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发表时间：
2011-10-15
影响因子：
3.5
通讯作者：
Kazantsev, Aleksey G.
中科院分区：
文献类型：
--
作者：
Maxwell, Michele M.;Tomkinson, Elizabeth M.;Kazantsev, Aleksey G.
Sirtuin 2（SIRT 2）是与酵母主寿命调节因子Sir 2同源的七种已知哺乳动物蛋白质脱乙酰基酶之一。近年来，沉默调节蛋白脱乙酰基酶已成为许多人类疾病的候选治疗靶点，包括代谢和年龄依赖性神经系统疾病。在非神经元细胞中，SIRT 2已显示出作为微管蛋白脱乙酰酶和细胞分裂和分化的关键调节剂起作用。然而，SIRT 2微管（MT）脱乙酰酶在分化的有丝分裂后神经元中的分布和功能在很大程度上仍然未知。在这里，我们显示了SIRT 2的特定亚型在哺乳动物中枢神经系统中的丰富和优先表达，并发现以前未表征的形式，SIRT2.3，在小鼠大脑和脊髓中表现出年龄依赖性的积累。此外，我们的研究揭示了内源性SIRT 2表达的焦点区域与原代小鼠皮层神经元中α-微管蛋白乙酰化的减少相关，并表明SIRT 2的脑富集种类可以在成熟神经元中充当主要的MT脱乙酰酶。最近的报道已经证明了受损的微管蛋白乙酰转移酶活性和神经退行性疾病之间的关联;从这个角度来看，我们的结果显示野生型小鼠中SIRT 2神经元MT脱乙酰酶的年龄依赖性积累表明微管蛋白乙酰化模式和衰老大脑之间的功能联系。
Sirtuin 2 (SIRT2) is one of seven known mammalian protein deacetylases homologous to the yeast master lifespan regulator Sir2. In recent years, the sirtuin protein deacetylases have emerged as candidate therapeutic targets for many human diseases, including metabolic and age-dependent neurological disorders. In non-neuronal cells, SIRT2 has been shown to function as a tubulin deacetylase and a key regulator of cell division and differentiation. However, the distribution and function of the SIRT2 microtubule (MT) deacetylase in differentiated, postmitotic neurons remain largely unknown. Here, we show abundant and preferential expression of specific isoforms of SIRT2 in the mammalian central nervous system and find that a previously uncharacterized form, SIRT2.3, exhibits age-dependent accumulation in the mouse brain and spinal cord. Further, our studies reveal that focal areas of endogenous SIRT2 expression correlate with reduced a-tubulin acetylation in primary mouse cortical neurons and suggest that the brain-enriched species of SIRT2 may function as the predominant MT deacetylases in mature neurons. Recent reports have demonstrated an association between impaired tubulin acetyltransferase activity and neurodegenerative disease; viewed in this light, our results showing age-dependent accumulation of the SIRT2 neuronal MT deacetylase in wild-type mice suggest a functional link between tubulin acetylation patterns and the aging brain.