IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome.
IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome.
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DOI：
10.1016/j.celrep.2022.111883
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发表时间：
2022-12-27
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
唐氏综合症（DS）是由21三体（T21）引起的遗传病，其特征是发育迟缓、认知障碍和多种神经系统疾病的风险增加。虽然在退行性椎体滑移中，终身神经退行性变的迹象得到了充分的证明，但这种表型的机制尚待阐明。在这里，我们报告了400多名研究参与者的不同队列的神经变性和神经炎症生物标志物，血浆蛋白质组学和免疫谱的多组学分析。我们发现胰岛素生长因子1 （IGF1）的消耗是与退行性椎体变性相关的首要生物特征，IGF1是生长和大脑发育的主要调节因子。患有T21的个体表现为生长激素下游慢性IGF1缺乏，与肿瘤坏死因子α (TNF-α)升高的特定炎症相关。个子较矮的DS患儿表现出更强的IGF1缺乏症，神经退行性变的生物标志物升高，自闭症和其他疾病的患病率增加。这些结果表明，IGF1信号的破坏可能导致退行性硬化症的生长发育迟缓和神经退行性变。唐氏综合症患者一生中表现出发育迟缓、慢性炎症和神经退行性变的升高迹象。Araya等人的研究表明，IGF1（人类发育的主要调节因子）的慢性缺乏与唐氏综合征的生长发育迟缓、特定炎症特征和神经退行性变迹象升高有关。
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by stunted growth, cognitive impairment, and increased risk of diverse neurological conditions. Although signs of lifelong neurodegeneration are well documented in DS, the mechanisms underlying this phenotype await elucidation. Here we report a multi-omics analysis of neurodegeneration and neuroinflammation biomarkers, plasma proteomics, and immune profiling in a diverse cohort of more than 400 research participants. We identified depletion of insulin growth factor 1 (IGF1), a master regulator of growth and brain development, as the top biosignature associated with neurodegeneration in DS. Individuals with T21 display chronic IGF1 deficiency downstream of growth hormone production, associated with a specific inflammatory profile involving elevated tumor necrosis factor alpha (TNF-α). Shorter children with DS show stronger IGF1 deficiency, elevated biomarkers of neurodegeneration, and increased prevalence of autism and other conditions. These results point to disruption of IGF1 signaling as a potential contributor to stunted growth and neurodegeneration in DS. Individuals with Down syndrome display stunted growth, chronic inflammation, and elevated signs of neurodegeneration across their lifespan. Araya et al. show that chronic deficiency in IGF1, a master regulator of human development, is associated with stunted growth, a specific inflammatory profile, and elevated signs of neurodegeneration in Down syndrome.
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影响因子：
16.6
作者：
Ashton NJ;Janelidze S;Al Khleifat A;Leuzy A;van der Ende EL;Karikari TK;Benedet AL;Pascoal TA;Lleó A;Parnetti L;Galimberti D;Bonanni L;Pilotto A;Padovani A;Lycke J;Novakova L;Axelsson M;Velayudhan L;Rabinovici GD;Miller B;Pariante C;Nikkheslat N;Resnick SM;Thambisetty M;Schöll M;Fernández-Eulate G;Gil-Bea FJ;López de Munain A;Al-Chalabi A;Rosa-Neto P;Strydom A;Svenningsson P;Stomrud E;Santillo A;Aarsland D;van Swieten JC;Palmqvist S;Zetterberg H;Blennow K;Hye A;Hansson O
通讯作者：
Hansson O
影响因子：
5.2
作者：
Allard JB;Duan C
通讯作者：
Duan C
DOI：
10.1016/s1474-4422(21)00129-0
发表时间：
2021-08
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Carmona-Iragui M;Alcolea D;Barroeta I;Videla L;Muñoz L;Van Pelt KL;Schmitt FA;Lightner DD;Koehl LM;Jicha G;Sacco S;Mircher C;Pape SE;Hithersay R;Clare ICH;Holland AJ;Nübling G;Levin J;Zaman SH;Strydom A;Rebillat AS;Head E;Blesa R;Lleó A;Fortea J
通讯作者：
Fortea J
影响因子：
25
作者：
Deliu, Elena;Arecco, Niccolo;Novarino, Gaia
通讯作者：
Novarino, Gaia
影响因子：
5.2
作者：
Annerén, G;Tuvemo, T;Gustafsson, J
通讯作者：
Gustafsson, J