神经退行性变中的遗传修饰因子
Genetic Modifiers in Neurodegeneration.
作者信息
Jain Nimansha, Chen-Plotkin Alice S
机构信息
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
出版信息
Curr Genet Med Rep. 2018 Mar;6(1):11-19. doi: 10.1007/s40142-018-0133-1. Epub 2018 Feb 5.
Abstract
PURPOSE OF REVIEW
To review the evidence for genetic modifier effects in the neurodegenerative diseases Huntington's Disease (HD), Frontotemporal Lobar Degeneration (FTLD), Alzheimer's Disease (AD), and Parkinson's Disease (PD).
RECENT FINDINGS
Increasingly, we understand human disease genetics less through the lens of single-locus/single-trait effects, and more through that of polygenic contributions to disease risk. In addition, specific examples of genetic modifier effects of the chromosome 7 gene on various target genes including those causal for Mendelian classes of FTLD - and - have emerged from both genetic cohort studies and mechanistic examinations of biological pathways.
SUMMARY
Here, we summarize the literature reporting genetic modifier effects in HD, FTLD, AD, and PD. We further contextualize reported genetic modifier effects in these diseases in terms of insight they may lend to the concept of a polygenic landscape for the major neurodegenerative diseases.
摘要
综述目的
回顾亨廷顿舞蹈病（HD）、额颞叶痴呆（FTLD）、阿尔茨海默病（AD）和帕金森病（PD）等神经退行性疾病中基因修饰效应的证据。
最新发现
我们越来越少地通过单基因座/单性状效应来理解人类疾病遗传学，而是更多地通过多基因对疾病风险的贡献来理解。此外，从基因队列研究和生物途径的机制研究中都发现了7号染色体基因对各种靶基因的基因修饰效应的具体例子，这些靶基因包括导致孟德尔型FTLD的那些基因。
总结
在此，我们总结了报道HD、FTLD、AD和PD中基因修饰效应的文献。我们进一步根据这些疾病中报道的基因修饰效应可能为主要神经退行性疾病的多基因格局概念提供的见解，将其置于背景中进行考量。
相似文献
1
Genetic Modifiers in Neurodegeneration.神经退行性变中的遗传修饰因子
Curr Genet Med Rep. 2018 Mar;6(1):11-19. doi: 10.1007/s40142-018-0133-1. Epub 2018 Feb 5.
2
Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes.额颞叶痴呆风险因子TMEM106B表达增加导致溶酶体中依赖C9orf72的改变。
Hum Mol Genet. 2016 Jul 1;25(13):2681-2697. doi: 10.1093/hmg/ddw127. Epub 2016 Apr 28.
3
Genetics of FTLD: overview and what else we can expect from genetic studies.额颞叶痴呆的遗传学：概述以及我们从遗传学研究中还能期待什么。
J Neurochem. 2016 Aug;138 Suppl 1:32-53. doi: 10.1111/jnc.13622.
4
HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease.HTT 基因中间等位基因与神经退行性变：与阿尔茨海默病相关的证据。
Neurobiol Aging. 2019 Apr;76:215.e9-215.e14. doi: 10.1016/j.neurobiolaging.2018.11.014. Epub 2018 Nov 28.
5
Diagnostic value of cerebrospinal fluid tau, neurofilament, and progranulin in definite frontotemporal lobar degeneration.脑脊液 tau、神经丝和颗粒蛋白在明确的额颞叶变性中的诊断价值。
Alzheimers Res Ther. 2018 Mar 20;10(1):31. doi: 10.1186/s13195-018-0364-0.
6
Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions.确定携带GRN突变和C9orf72重复扩增的额颞叶痴呆患者中TMEM106B变异体之间的关联。
Neurobiol Aging. 2014 Nov;35(11):2658.e1-2658.e5. doi: 10.1016/j.neurobiolaging.2014.06.023. Epub 2014 Jun 28.
7
Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration.额颞叶变性患者的癌症患病率较低。
J Alzheimers Dis. 2018;62(2):789-794. doi: 10.3233/JAD-170854.
8
Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders.神经退行性变的途径：来自阿尔茨海默病、帕金森病及相关疾病全基因组关联研究的机制洞察
Am J Neurodegener Dis. 2013 Sep 18;2(3):145-75.
9
Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency.颗粒蛋白前体缺乏的老年小鼠 TMEM106B 水平升高可加剧脂褐素堆积和溶酶体功能障碍。
Acta Neuropathol Commun. 2017 Jan 26;5(1):9. doi: 10.1186/s40478-017-0412-1.
10
Serum progranulin levels in patients with frontotemporal lobar degeneration and Alzheimer's disease: detection of GRN mutations in a Spanish cohort.血清颗粒蛋白前体水平在额颞叶变性和阿尔茨海默病患者中的变化：在西班牙队列中检测 GRN 突变。
J Alzheimers Dis. 2012;31(3):581-91. doi: 10.3233/JAD-2012-112120.
引用本文的文献
1
Emerging Concepts in Diagnosis, Pathologic Features, and Treatment of Limbic-Predominant Amnestic Neurodegenerative Syndrome (LANS): A Narrative Review.边缘叶为主型遗忘性神经退行性综合征（LANS）的诊断、病理特征及治疗的新观念：一篇综述
Adv Ther. 2025 Aug 29. doi: 10.1007/s12325-025-03337-x.
2
Unraveling human transferrin-tryptamine interactions: a computational and biophysical approach to Alzheimer's disease therapeutics.解析人转铁蛋白-色胺相互作用：一种针对阿尔茨海默病治疗的计算与生物物理方法
Front Pharmacol. 2025 Mar 19;16:1540736. doi: 10.3389/fphar.2025.1540736. eCollection 2025.
3
Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.神经退行性疾病的分子机制与生物标志物：综述
Mol Biol Rep. 2025 Mar 26;52(1):337. doi: 10.1007/s11033-025-10463-w.
4
Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens.审视神经退行性疾病：通过多组学视角解码复杂的遗传结构
Hum Genomics. 2024 Dec 31;18(1):141. doi: 10.1186/s40246-024-00704-7.
5
Computational Studies Applied to Linalool and Citronellal Derivatives Against Alzheimer's and Parkinson's Disorders: A Review with Experimental Approach.计算研究在芳樟醇和香茅醛衍生物治疗阿尔茨海默病和帕金森病中的应用：实验方法综述。
Curr Neuropharmacol. 2023;21(4):842-866. doi: 10.2174/1570159X21666230221123059.
6
APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology.载脂蛋白 E2 在没有阿尔茨海默病病理学的情况下加剧 TDP-43 相关毒性。
Ann Neurol. 2023 Apr;93(4):830-843. doi: 10.1002/ana.26580. Epub 2023 Jan 10.
7
A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics.常见神经退行性疾病综述：当前治疗方法及纳米疗法的潜在作用。
Int J Mol Sci. 2022 Feb 6;23(3):1851. doi: 10.3390/ijms23031851.
8
Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases.运用先进数据科学从靶向测序面板中识别复发性遗传模式：散发性和遗传性神经退行性疾病的案例研究
BMC Med Genomics. 2022 Feb 10;15(1):26. doi: 10.1186/s12920-022-01173-4.
9
Lysosomal dysfunction in neurodegeneration: emerging concepts and methods.神经退行性疾病中的溶酶体功能障碍：新兴概念与方法。
Trends Neurosci. 2022 Mar;45(3):184-199. doi: 10.1016/j.tins.2021.12.004. Epub 2022 Jan 13.
10
Huntington disease: Advances in the understanding of its mechanisms.亨廷顿舞蹈症：对其发病机制理解的进展
Clin Park Relat Disord. 2020 May 6;3:100056. doi: 10.1016/j.prdoa.2020.100056. eCollection 2020.
本文引用的文献
1
A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression.TMEM106B附近与痴呆症相关的风险变异改变染色质结构和基因表达。
Am J Hum Genet. 2017 Nov 2;101(5):643-663. doi: 10.1016/j.ajhg.2017.09.004. Epub 2017 Oct 19.
2
genotype and early β-amyloid accumulation in older adults without dementia.老年非痴呆人群的基因型与早期β-淀粉样蛋白积聚
Neurology. 2017 Sep 5;89(10):1028-1034. doi: 10.1212/WNL.0000000000004336. Epub 2017 Aug 9.
3
Unlocking the mystery of biomarkers: A brief introduction, challenges and opportunities in Parkinson Disease.解锁生物标志物的奥秘：帕金森病的简介、挑战与机遇。
Parkinsonism Relat Disord. 2018 Jan;46 Suppl 1(Suppl 1):S15-S18. doi: 10.1016/j.parkreldis.2017.07.021. Epub 2017 Jul 22.
4
From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health.从豌豆到疾病：修饰基因、网络弹性与健康遗传学
Am J Hum Genet. 2017 Aug 3;101(2):177-191. doi: 10.1016/j.ajhg.2017.06.004.
5
Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice.跨膜蛋白106B缺失改善了颗粒蛋白前体缺陷小鼠的溶酶体及额颞叶痴呆相关表型。
Neuron. 2017 Jul 19;95(2):281-296.e6. doi: 10.1016/j.neuron.2017.06.026.
6
A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.一种常见的单倍型会降低髓系细胞中PU.1的表达，并延缓阿尔茨海默病的发病。
Nat Neurosci. 2017 Aug;20(8):1052-1061. doi: 10.1038/nn.4587. Epub 2017 Jun 19.
7
An Expanded View of Complex Traits: From Polygenic to Omnigenic.复杂性状的扩展观点：从多基因到泛基因
Cell. 2017 Jun 15;169(7):1177-1186. doi: 10.1016/j.cell.2017.05.038.
8
Age-related penetrance of the C9orf72 repeat expansion.与年龄相关的 C9orf72 重复扩展的外显率。
Sci Rep. 2017 May 18;7(1):2116. doi: 10.1038/s41598-017-02364-1.
9
Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.认知功能与神经病理负担分离相关基因的鉴定：遗传、表观遗传和转录数据的多步骤分析
PLoS Med. 2017 Apr 25;14(4):e1002287. doi: 10.1371/journal.pmed.1002287. eCollection 2017 Apr.
10
Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes.人类大脑皮层的差异衰老分析鉴定出 TMEM106B 和 GRN 中的变体，这些变体调节衰老表型。
Cell Syst. 2017 Apr 26;4(4):404-415.e5. doi: 10.1016/j.cels.2017.02.009. Epub 2017 Mar 18.
Zotero 插件