致病性PPP2R5D变异破坏患者源性神经元的神经元发育和神经突生长,这可以通过等位基因特异性敲低来逆转。

IF 3.3 Q2 GENETICS & HEREDITY
Randee E Young, Michael V Zuccaro, Charles A LeDuc, Noelle D Germain, Tae Hyun Kim, Patrick Sarmiere, Wendy K Chung
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引用次数: 0

摘要

神经发育障碍(ndd)治疗的一个重要障碍是对疾病机制的理解有限。PPP2R5D的杂合错义变异导致Houge-Janssens综合征1,这是一种罕见的NDD,以大头畸形、发育迟缓、智力残疾、癫痫发作、自闭症谱系障碍和早发性帕金森病为特征。本研究调查了致病性PPP2R5D变异对神经元发育的影响,并评估了等位基因特异性敲除作为一种潜在的治疗策略。来自携带E198K和E420K变体的个体的诱导多能干细胞,以及crispr校正的等基因对照,分化为神经祖细胞和皮质谷氨酸能神经元。患者来源的神经祖细胞是高度增殖的,从这些细胞分化出来的谷氨酸能神经元表现出增加的神经突生长。值得注意的是,在缺乏PPP2R5D的神经元中没有观察到神经元过度生长表型,这表明这种疾病不是由功能丧失引起的。与等基因对照相比,来自患者系的谷氨酸能神经元的rna测序揭示了神经元发育、突触信号传导和轴突引导的关键通路的中断。为了靶向致病性转录本,设计了反义寡核苷酸(ASOs)来选择性地敲除最常见的致病错义变异E198K等位基因。最有效的ASOs逆转了患者源性神经元的神经突生长缺陷。这些发现揭示了ppp2r5d相关NDD的分子机制,并支持等位基因特异性敲除作为潜在的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown.

A significant barrier to the treatment of neurodevelopmental disorders (NDDs) is a limited understanding of disease mechanisms. Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease. This study investigated the impact of pathogenic PPP2R5D variants on neuronal development and evaluated allele-specific knockdown as a potential therapeutic strategy. Induced pluripotent stem cells derived from individuals carrying the E198K and E420K variants, along with CRISPR-corrected isogenic controls, were differentiated into neural progenitors and cortical glutamatergic neurons. Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth. Notably, neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function. RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. To target pathogenic transcripts, antisense oligonucleotides (ASOs) were designed to selectively knock down the E198K allele, the most common disease-causing missense variant. The most effective ASOs reversed neurite outgrowth defects in patient-derived neurons. These findings uncover molecular mechanisms underlying PPP2R5D-related NDDs and support allele-specific knockdown as a potential therapeutic approach.

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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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