Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.
Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.
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DOI：
10.1093/brain/awad243
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发表时间：
2023-12-01
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肌萎缩侧索硬化症（ALS）是一种以上、下运动神经元进行性丧失为特征的神经退行性疾病。ALS属于额颞叶痴呆的发病疾病谱，称为ALS-额颞叶谱系障碍（ALS-FTSD）。对于与ALS-FTSD相关的突变，如C9 orf 72六核苷酸重复扩增，与沿着该谱的异质性相关的分子因素需要进一步表征。在这里，使用有针对性的NanoString分子条形码的方法，我们询问神经炎症失调和异质性的基因表达水平在死后的运动皮质组织从临床异质性C9-ALS-FTSD的情况下的队列。我们在C9-ALS-FTSD中鉴定了20个失调基因，其中小胶质细胞和炎症反应基因集富集。选择与可用临床指标具有显著相关性的两个基因进行验证：FKBP 5，认知功能的相关性，和脑源性神经营养因子（BDNF），疾病持续时间的相关性。FKBP 5及其信号传导伴侣NF-κB似乎具有细胞类型特异性染色分布，在C9-ALS-FTSD中具有活化的（即核）NF-κB免疫反应性。使用BaseScope™原位杂交证实，与疾病持续时间相关的BDNF表达在疾病持续时间长的个体中高于疾病持续时间短的个体。我们的分析还揭示了两个不同的神经炎性小组签名（NPS 1和NPS 2），由促炎性，轴突运输和突触信号传导途径的表达方向划定。我们比较了C9-ALS-FTSD病例与来自散发性ALS和SOD 1-ALS队列的病例之间的差异，并在所有队列中鉴定了NPS 1和NPS 2。此外，一个亚组也能够将来自独立C9-ALS和散发性ALS队列的公开可用的RNA测序数据分成两个炎性亚组。重要的是，炎症亚组并没有明显地与可用的人口统计学、遗传学、临床或病理学特征分离，突出了临床试验中分子分层对于炎症亚组鉴定的价值。因此，我们的研究结果强调了根据ALS-FTSD队列之间和队列内存在的不同分子特征定制治疗方法的重要性。Rifai等人描述了ALS患者脑组织中的神经炎症，并确定了两种不同的炎症特征，这似乎与遗传学或临床症状无关。这些签名对于临床试验分层以进行适当的结局测量可能是重要的。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts. Rifai et al. characterize neuroinflammation in brain tissue from patients with ALS and identify two distinct inflammatory signatures, which do not appear to segregate with genetics or clinical symptoms. These signatures may be important for the stratification of clinical trials for appropriate outcome measurement.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
25
作者：
Eitan C;Siany A;Barkan E;Olender T;van Eijk KR;Moisse M;Farhan SMK;Danino YM;Yanowski E;Marmor-Kollet H;Rivkin N;Yacovzada NS;Hung ST;Cooper-Knock J;Yu CH;Louis C;Masters SL;Kenna KP;van der Spek RAA;Sproviero W;Al Khleifat A;Iacoangeli A;Shatunov A;Jones AR;Elbaz-Alon Y;Cohen Y;Chapnik E;Rothschild D;Weissbrod O;Beck G;Ainbinder E;Ben-Dor S;Werneburg S;Schafer DP;Brown RH Jr;Shaw PJ;Van Damme P;van den Berg LH;Phatnani H;Segal E;Ichida JK;Al-Chalabi A;Veldink JH;Project MinE ALS Sequencing Consortium;NYGC ALS Consortium;Hornstein E
通讯作者：
Hornstein E
影响因子：
7.3
作者：
Gregory, Jenna M.;Livesey, Matthew R.;Smith, Colin
通讯作者：
Smith, Colin
影响因子：
5
作者：
Gregory, J. M.;Elliott, E.;Smith, C.
通讯作者：
Smith, C.
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.