Ozarkar Siddhi S, Patel Ridthi K-R, Vulli Tasmai, Smith Audrey L, Shen Mark D, Burette Alain C, Philpot Benjamin D, Styner Martin A, Hazlett Heather C
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Res Sq. 2024 Aug 9:rs.3.rs-4681861. doi: 10.21203/rs.3.rs-4681861/v1.
Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still not well characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the underlying neuropathology by examining the progression of myelination in an AS mouse model.
We conducted magnetic resonance imaging (MRI) on children with AS (n=32) and neurotypical controls (n=99) aged 0.5-12 years. In parallel, we examined myelination in postnatal maternal-null mice ( ; AS model), paternal-null mice ( ), and wildtype controls ( ) using immunohistochemistry, Western blotting, and electron microscopy.
Our data revealed that AS individuals exhibit significant reductions in brain volume by ~1 year of age, with WM reduced by 26% and gray matter by 21% by 6-12 years of age-approximately twice the reductions observed in the adult AS mouse model. In our AS mouse model, we saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal any abnormalities in myelinated or unmyelinated axons.
It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS.
This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show that these deficits may be associated with delayed onset of myelination due to the loss of neuronal (but not glial) UBE3A. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments.
天使综合征（AS）是一种因母源基因缺失导致的严重神经发育障碍，其特征为脑白质（WM）改变。WM异常的程度似乎与临床症状的严重程度相关，但这些缺陷仍未得到充分表征或理解。本研究首次对AS患儿的WM体积减少进行了大规模测量。此外，我们通过研究AS小鼠模型中髓鞘形成的进程来探究潜在的神经病理学机制。
我们对32名年龄在0.5至12岁的AS患儿和99名神经典型对照者进行了磁共振成像（MRI）。同时，我们使用免疫组织化学、蛋白质印迹法和电子显微镜检查了产后母源缺失小鼠（；AS模型）、父源缺失小鼠（）和野生型对照小鼠（）的髓鞘形成情况。
我们的数据显示，AS个体在约1岁时脑体积显著减小，到6至12岁时WM减少26%，灰质减少21%，这大约是成年AS小鼠模型中观察到的减少量的两倍。在我们的AS小鼠模型中，我们发现髓鞘形成开始出现全球性延迟，这种延迟在数天内恢复正常（可能相当于人类发育中的数月或数年）。这种髓鞘形成延迟是由神经元中UBE3A的缺失而非少突胶质细胞中UBE3A单倍剂量不足引起的。有趣的是，超微结构分析未发现有髓或无髓轴突存在任何异常。
难以将在AS模型小鼠中观察到的髓鞘形成延迟的时间和持续时间外推至AS个体。
本研究揭示WM缺陷是AS患儿的一个标志，首次证明这些缺陷在1岁时就已明显。在AS小鼠模型中的平行研究表明，这些缺陷可能与神经元（而非神经胶质细胞）UBE3A缺失导致的髓鞘形成延迟有关。这些发现强调了WM作为干预治疗靶点以及追踪AS进展和潜在治疗效果的有价值生物标志物的潜力。
