Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
Cells. 2021 Feb 10;10(2):368. doi: 10.3390/cells10020368.
Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both and gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of resulted in a female-specific motor-coordination defect, whereas disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.
腺苷二磷酸核糖基化 (ADP-ribosylation; ADPr)，即将 ADP-核糖基部分添加到蛋白质和核酸上，是一种高度保守的修饰，涉及广泛的细胞功能，从病毒防御、DNA 损伤反应 (DDR)、代谢、致癌作用和神经生物学。在这里，我们研究了 MACROD1 和 MACROD2（单 ADP-核糖基水解酶 1 和 2），这是两种了解最少的 ADPr-单水解酶。据报道，MACROD1 主要定位于线粒体，而基因座与自闭症、注意力缺陷多动障碍 (ADHD) 和精神分裂症等各种神经疾病有关；然而，破坏这些蛋白质在哺乳动物行为背景下的潜在意义尚不清楚。因此，在这里，我们在一系列定义明确的自发行为测试范式中分析了 和 基因敲除 (KO) 小鼠模型。的缺失导致雌性特异性运动协调缺陷，而 的破坏与多动有关，随着年龄的增长变得更加明显，同时还伴有类似帕金森病的步态。这些数据揭示了 ADPr-单水解酶在与线粒体和神经精神疾病相关的行为方面的重要性的新见解。
