Manek Rachna, Huang Weixiao, Huang Yinyin, Guo Lilu, Cornell Cathleen S, Shazeeb Mohammed Salman, Verbitsky Alexander, Jackson Robert, Johnson Jennifer, Berthelette Patricia, Yu Dan, Pfister Edith L, Bangari Dinesh, Ying Xiaoyou, Kumar Dinesh, Mueller Christian, Kyostio-Moore Sirkka
Genomic Medicine Unit, Sanofi, Waltham, MA, USA.
Translational Sciences, Sanofi, Cambridge, MA, USA.
Mol Ther. 2025 Sep 3;33(9):4303-4319. doi: 10.1016/j.ymthe.2025.06.020. Epub 2025 Jun 14.
Phenylketonuria (PKU) is a genetic defect caused by lack of the liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood phenylalanine (Phe) levels and neurotoxicity, which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering by analyzing the corpus callosum (CC) of adult Pah (PAH-deficient) mice. MRI and immunostaining demonstrated a significant reduction in CC volume in Pah mice. Treatment with an adeno-associated vector (AAV) encoding mouse PAH for 3.5 months improved but did not completely normalize CC volume. Total cholesterol, a major component of myelin, was unchanged in the CC of Pah mouse, while some sterol intermediates were significantly reduced by treatment. Single-nuclei transcriptomics showed an upregulation of oxidative stress-related pathways and increased expression of transthyretin, ApoE, Cst3, and Cd81 in CC in Pah mice. Normalization of blood Phe restored gene expression to levels comparable to those of heterozygous mice and was associated with the generation of differentiated myelin-producing oligodendrocyte subtypes and neuroprotective astrocytes. In summary, Pah mice showed white matter abnormalities and changes in transcriptome and sterol profiles, which were partially corrected by the normalization of blood Phe.
苯丙酮尿症（PKU）是一种由肝脏缺乏苯丙氨酸羟化酶（PAH）引起的遗传缺陷。这种缺陷导致血液中苯丙氨酸（Phe）水平升高和神经毒性，表现为脑容量减小、神经递质水平降低和髓鞘形成减少。本研究的目的是通过分析成年Pah（PAH缺陷）小鼠的胼胝体（CC）来研究脑髓鞘形成缺陷及其在血液Phe降低后的可逆性。MRI和免疫染色显示Pah小鼠的CC体积显著减小。用编码小鼠PAH的腺相关载体（AAV）治疗3.5个月可改善但不能使CC体积完全恢复正常。髓鞘的主要成分总胆固醇在Pah小鼠的CC中未发生变化，而一些固醇中间体经治疗后显著降低。单核转录组学显示Pah小鼠CC中氧化应激相关途径上调，转甲状腺素蛋白、载脂蛋白E、Cst3和Cd81的表达增加。血液Phe正常化将基因表达恢复到与杂合小鼠相当的水平，并与分化的产生髓鞘的少突胶质细胞亚型和神经保护性星形胶质细胞的生成有关。总之，Pah小鼠表现出白质异常以及转录组和固醇谱的变化，这些变化在血液Phe正常化后得到了部分纠正。
