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Endolysosome and autophagy dysfunction in Alzheimer disease
Autophagy ( IF 14.6 ) Pub Date : 2021-08-25 , DOI: 10.1080/15548627.2021.1963630
Christy Hung 1 , Frederick J Livesey 1
Affiliation  

ABSTRACT

Abnormalities of the neuronal endolysosome and macroautophagy/autophagy system are an early and prominent feature of Alzheimer disease (AD). SORL1 is notable as a gene in which mutations are causal for a rare, autosomal dominant form of AD, and also variants that increase the risk of developing the common form of late-onset AD. In our recent study, we used patient-derived stem cells and CRISPR engineering to study the effects of SORL1 mutations on the endolysosome and autophagy system in human forebrain neurons. SORL1 mutations causal for monogenic AD are typically truncating mutations, and we found, using stem cells generated from an individual with dementia due to a heterozygous SORL1 truncation mutation, that this class of mutation results in SORL1 haploinsufficiency. Reducing SORL1 protein by half results in disrupted endosomal trafficking in patient-derived neurons, which we confirmed by studying the endolysosomal system in isogenic CRISPR-engineered SORL1 heterozygous null neurons. We also found that SORL1 homozygous null neurons develop more severe phenotypes, with endosome abnormalities, lysosome dysfunction and defects in the degradative phase of autophagy. Endolysosome and autophagy defects in SORL1 mutant neurons are dependent on APP, a key AD gene, as they are rescued by extracellular antisense oligonucleotides that reduce APP protein.



中文翻译:

阿尔茨海默病的内溶酶体和自噬功能障碍

摘要

神经元内溶酶体和巨自噬/自噬系统的异常是阿尔茨海默病 (AD) 的早期和突出特征。SORL1是一个值得注意的基因,其中突变是导致罕见的常染色体显性 AD 形式的原因,也是增加发展为常见形式的迟发性 AD 风险的变体。在我们最近的研究中,我们使用患者来源的干细胞和 CRISPR 工程来研究SORL1突变对人类前脑神经元内溶酶体和自噬系统的影响。导致单基因 AD 的SORL1突变通常是截断突变,我们发现,使用由杂合SORL1导致的痴呆患者产生的干细胞截断突变,这类突变导致 SORL1 单倍体不足。将 SORL1 蛋白减少一半会导致患者衍生神经元的内体运输中断,我们通过研究同基因 CRISPR 工程化的SORL1杂合无效神经元中的内溶酶体系统证实了这一点。我们还发现SORL1纯合无效神经元发展出更严重的表型,包括内体异常、溶酶体功能障碍和自噬降解阶段的缺陷。SORL1突变神经元中的内溶酶体和自噬缺陷依赖于关键的 AD 基因APP,因为它们被减少 APP 蛋白的细胞外反义寡核苷酸所拯救。

更新日期:2021-08-25
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