Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, Gelderland, The Netherlands.
Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behavior, Nijmegen, Gelderland, The Netherlands.
Autophagy. 2024 Jan;20(1):15-28. doi: 10.1080/15548627.2023.2250217. Epub 2023 Sep 6.
Macroautophagy/autophagy is an evolutionarily highly conserved catabolic process that is important for the clearance of cytosolic contents to maintain cellular homeostasis and survival. Recent findings point toward a critical role for autophagy in brain function, not only by preserving neuronal health, but especially by controlling different aspects of neuronal development and functioning. In line with this, mutations in autophagy-related genes are linked to various key characteristics and symptoms of neurodevelopmental disorders (NDDs), including autism, micro-/macrocephaly, and epilepsy. However, the group of NDDs caused by mutations in autophagy-related genes is relatively small. A significant proportion of NDDs are associated with mutations in genes encoding epigenetic regulatory proteins that modulate gene expression, so-called chromatinopathies. Intriguingly, several of the NDD-linked chromatinopathy genes have been shown to regulate autophagy-related genes, albeit in non-neuronal contexts. From these studies it becomes evident that tight transcriptional regulation of autophagy-related genes is crucial to control autophagic activity. This opens the exciting possibility that aberrant autophagic regulation might underly nervous system impairments in NDDs with disturbed epigenetic regulation. We here summarize NDD-related chromatinopathy genes that are known to regulate transcriptional regulation of autophagy-related genes. Thereby, we want to highlight autophagy as a candidate key hub mechanism in NDD-related chromatinopathies. ADNP: activity dependent neuroprotector homeobox; ASD: autism spectrum disorder; ATG: AutTophaGy related; CpG: cytosine-guanine dinucleotide; DNMT: DNA methyltransferase; EHMT: euchromatic histone lysine methyltransferase; EP300: E1A binding protein p300; EZH2: enhancer of zeste 2 polycomb repressive complex 2 subunit; H3K4me3: histone 3 lysine 4 trimethylation; H3K9me1/2/3: histone 3 lysine 9 mono-, di-, or trimethylation; H3K27me2/3: histone 3 lysine 27 di-, or trimethylation; hiPSCs: human induced pluripotent stem cells; HSP: hereditary spastic paraplegia; ID: intellectual disability; KANSL1: KAT8 regulatory NSL complex subunit 1; KAT8: lysine acetyltransferase 8; KDM1A/LSD1: lysine demethylase 1A; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NDD: neurodevelopmental disorder; PHF8: PHD finger protein 8; PHF8-XLID: PHF8-X linked intellectual disability syndrome; PTM: post-translational modification; SESN2: sestrin 2; YY1: YY1 transcription factor; YY1AP1: YY1 associated protein 1.
自噬是一种进化上高度保守的分解代谢过程，对于清除细胞质内容物以维持细胞内稳态和存活非常重要。最近的研究结果表明，自噬在大脑功能中起着关键作用，不仅通过维持神经元的健康，而且特别通过控制神经元发育和功能的不同方面。与此一致的是，自噬相关基因的突变与各种神经发育障碍 (NDD) 的关键特征和症状有关，包括自闭症、小头畸形/巨脑畸形和癫痫。然而，由自噬相关基因突变引起的 NDD 组相对较小。相当一部分 NDD 与编码表观遗传调节蛋白的基因突变有关，这些基因调节基因表达，即所谓的染色质病。有趣的是，一些与 NDD 相关的染色质病基因已被证明可以调节自噬相关基因，尽管是在非神经元环境中。这些研究表明，自噬相关基因的转录调控是控制自噬活性的关键。这为异常的自噬调节可能是 NDD 中神经损伤的基础提供了令人兴奋的可能性，这些 NDD 存在表观遗传调节紊乱。我们在这里总结了已知调节自噬相关基因转录调控的与 NDD 相关的染色质病基因。通过这种方式，我们想强调自噬作为与 NDD 相关染色质病的候选关键枢纽机制。ADNP：活性依赖神经保护同源盒；ASD：自闭症谱系障碍；ATG：自噬相关；CpG：胞嘧啶-鸟嘌呤二核苷酸；DNMT：DNA 甲基转移酶；EHMT：euchromatic histone lysine methyltransferase；EP300：E1A 结合蛋白 p300；EZH2：增强子的 zeste 2 多梳抑制复合物 2 亚基；H3K4me3：组蛋白 3 赖氨酸 4 三甲基化；H3K9me1/2/3：组蛋白 3 赖氨酸 9 单、二或三甲基化；H3K27me2/3：组蛋白 3 赖氨酸 27 二甲基化或三甲基化；hiPSCs：人类诱导多能干细胞；HSP：遗传性痉挛性截瘫；ID：智力障碍；KANSL1：KAT8 调节 NSL 复合物亚基 1；KAT8：赖氨酸乙酰转移酶 8；KDM1A/LSD1：赖氨酸去甲基酶 1A；MAP1LC3B：微管相关蛋白 1 轻链 3β；MTOR：雷帕霉素机制靶标激酶；MTORC1：雷帕霉素靶标复合物 1；NDD：神经发育障碍；PHF8：PHD 指蛋白 8；PHF8-XLID：PHF8-X 连锁智力障碍综合征；PTM：翻译后修饰；SESN2： sestrin 2；YY1：YY1 转录因子；YY1AP1：YY1 相关蛋白 1。
