Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Neurobiol Aging. 2018 Jun;66:179.e17-179.e29. doi: 10.1016/j.neurobiolaging.2018.01.015. Epub 2018 Feb 2.
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.
孟德尔成人发病型脑白质营养不良是一组罕见的遗传性进行性神经退行性疾病，影响中枢神经系统的白质。其中，常染色体显性和隐性脑动脉病伴皮质下梗死和脑白质病、脑视网膜血管病、异染性脑白质营养不良、遗传性弥漫性脑白质病伴球体、进行性脑白质病以快速进行性痴呆为主要特征，分别由 NOTCH3、HTRA1、TREX1、ARSA、CSF1R、EIF2B1、EIF2B2、EIF2B3、EIF2B4 和 EIF2B5 的突变引起。鉴于这些疾病的罕见发病率和缺乏明确的诊断特征，脑白质营养不良经常被误诊为常见的散发性痴呆疾病，如阿尔茨海默病（AD），这就提出了一个问题，即这些重叠的表型是否可以用共同的遗传风险因素来解释。为了研究这一有趣的假设，我们结合了基因表达分析（1）在 6 种不同的 AD 小鼠模型（APPPS1、HOTASTPM、HETASTPM、TPM、TAS10 和 TAU）的 5 个不同发育阶段（胚胎[E15]、2、4、8 和 18 个月），（2）在 APPPS1 原代皮质神经元在应激条件下（缺氧-葡萄糖剥夺）以及在由 332 名高加索晚发性 AD 患者和 676 名高加索老年对照组成的队列中进行基于单变体和单基因的（c-alpha 测试和序列核关联测试（SKAT））遗传筛选。CSF1R 在具有广泛 Aβ 致密核心斑块病理学的老年 HOTASTPM 小鼠的皮质和海马中显著过表达（log2FC > 1，调整后 p 值 < 0.05）。我们在由来自英国的 465 名 AD 和轻度认知障碍（MCI）白种人患者组成的发现和验证队列中鉴定出 CSF1R TK 结构域中的 3 种可能的致病性突变（p.L868R、p.Q691H 和 p.H703Y）。此外，NOTCH3 在 c-alpha 测试中是一个显著的命中（调整后 p 值= 0.01）。成人发病型孟德尔脑白质营养不良基因不是 AD 中常见的相关因素。然而，我们的研究表明，NOTCH3、CSF1R 和散发性晚发性 AD 之间存在潜在的致病联系，这值得进一步研究。
