miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer's model.
miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer's model.
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miR-277靶向促凋亡基因hid改善阿尔茨海默病模型中Aβ42介导的神经退行性变
DOI：
10.1038/s41419-023-06361-3
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发表时间：
2024-01-18
影响因子：
9
通讯作者：
Singh, Amit
中科院分区：
文献类型：
--
作者：
Deshpande, Prajakta;Chen, Chao-Yi;Chimata, Anuradha Venkatakrishnan;Li, Jian-Chiuan;Sarkar, Ankita;Yeates, Catherine;Chen, Chun-Hong;Kango-Singh, Madhuri;Singh, Amit
阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，表现出认知功能下降，迄今为止还没有治愈。AD的原因之一是淀粉样蛋白-β 42（Aβ42）斑块的积累，其触发异常基因表达和信号传导，导致神经元细胞通过未知机制死亡。人Aβ42在果蝇视网膜发育中的错误表达表现出AD样神经病理学小的非编码RNA，microRNA（miRNA），转录后调节其靶基因的表达，从而调节不同的信号通路。在正向遗传筛选中，我们鉴定了miR-277（人类直系同源物为hsa-miR-3660）作为Aβ42介导的神经变性的遗传修饰剂。miR-277的功能丧失增强了Aβ42介导的神经变性。而在GMR > Aβ42背景下，miR-277的功能获得下调细胞死亡以维持神经元的数量，从而恢复视网膜轴突靶向缺陷，表明功能性拯救。此外，miR-277的功能获得挽救了在GMR > Aβ42背景中观察到的羽化和攀爬测定缺陷。因此，miR-277的功能获得性在结构上和功能上挽救了Aβ42介导的神经变性。此外，我们确定了头部退化缺陷（HID），一种进化上保守的促凋亡基因，作为miR-277的靶点之一，并使用荧光素酶和qPCR检测验证了这些结果。在GMR > Aβ42背景中，与单独的GMR > Aβ42背景相比，miR-277的功能获得导致hid转录物水平降低至其水平的三分之一。在这里，我们提供了一种新的分子机制，其中miR-277靶向并下调促凋亡基因，hid，转录水平，通过阻断细胞死亡来挽救Aβ42介导的神经变性。这些研究阐明了在人类神经退行性疾病中观察到的Aβ42蓄积后介导细胞死亡反应的分子机制，并为神经退行性疾病提供了新的治疗靶点。
Alzheimer’s disease (AD), an age-related progressive neurodegenerative disorder, exhibits reduced cognitive function with no cure to date. One of the reasons for AD is the accumulation of Amyloid-beta 42 (Aβ42) plaque(s) that trigger aberrant gene expression and signaling, which results in neuronal cell death by an unknown mechanism(s). Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD-like neuropathology. Small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate the expression of their target genes and thereby regulate different signaling pathways. In a forward genetic screen, we identified miR-277 (human ortholog is hsa-miR-3660) as a genetic modifier of Aβ42-mediated neurodegeneration. Loss-of-function of miR-277 enhances the Aβ42-mediated neurodegeneration. Whereas gain-of-function of miR-277 in the GMR > Aβ42 background downregulates cell death to maintain the number of neurons and thereby restores the retinal axonal targeting defects indicating the functional rescue. In addition, gain-of-function of miR-277 rescues the eclosion- and climbing assays defects observed in GMR > Aβ42 background. Thus, gain-of-function of miR-277 rescues both structurally as well as functionally the Aβ42-mediated neurodegeneration. Furthermore, we identified head involution defective (hid), an evolutionarily conserved proapoptotic gene, as one of the targets of miR-277 and validated these results using luciferase- and qPCR -assays. In the GMR > Aβ42 background, the gain-of-function of miR-277 results in the reduction of hid transcript levels to one-third of its levels as compared to GMR > Aβ42 background alone. Here, we provide a novel molecular mechanism where miR-277 targets and downregulates proapoptotic gene, hid, transcript levels to rescue Aβ42-mediated neurodegeneration by blocking cell death. These studies shed light on molecular mechanism(s) that mediate cell death response following Aβ42 accumulation seen in neurodegenerative disorders in humans and provide new therapeutic targets for neurodegeneration.
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影响因子：
2.7
作者：
Tanaka-Matakatsu, Miho;Xu, Jinhua;Cheng, Leping;Du, Wei
通讯作者：
Du, Wei
影响因子：
12.7
作者：
Bouter Y;Dietrich K;Wittnam JL;Rezaei-Ghaleh N;Pillot T;Papot-Couturier S;Lefebvre T;Sprenger F;Wirths O;Zweckstetter M;Bayer TA
通讯作者：
Bayer TA
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
3.7
作者：
Steffensmeier AM;Tare M;Puli OR;Modi R;Nainaparampil J;Kango-Singh M;Singh A
通讯作者：
Singh A
影响因子：
4.8
作者：
Creagh, EM;Murphy, BM;Martin, SJ
通讯作者：
Martin, SJ