Molecular origin of somatostatin-positive neuron vulnerability.
Molecular origin of somatostatin-positive neuron vulnerability.
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DOI：
10.1038/s41380-022-01463-4
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发表时间：
2022-04
影响因子：
11
通讯作者：
Sibille, Etienne
中科院分区：
文献类型：
--
作者：
Tomoda, Toshifumi;Sumitomo, Akiko;Newton, Dwight;Sibille, Etienne
生长抑素 (SST) 减少和 SST 阳性 (SST+) 神经元功能障碍是神经系统疾病的标志，并与情绪障碍相关，但 SST+ 神经元脆弱性的分子起源尚不清楚。使用慢性心理社会压力作为诱发啮齿类动物行为情绪升高的范例，我们报告了通过前额皮质中内质网（ER）的未折叠蛋白反应（UPR）加剧或ER应激，SST+神经元的选择性脆弱性。接下来，我们证明，通过基因抑制 SST+ 神经元（而非锥体神经元）的 ER 应激，可以使社会心理压力引起的行为情绪正常化。在寻找介导SST+神经元脆弱性的内在因素时，我们发现SST+神经元中SST前体蛋白（preproSST）的强制表达，模仿心理社会压力引起的早期蛋白质组变化，诱导内质网应激，而成熟的SST或处理能力不强的preproSST则不会。生化分析进一步表明，在升高的 ER 应激条件下，社会心理压力会诱导 SST 蛋白聚集。这些结果表明，在持续或过度激活 UPR 的情况下，ER 中的 SST 处理是 SST+ 神经元固有的脆弱因素，因此会对 SST+ 神经元功能产生负面影响。结合对糖尿病等重大疾病的观察，前胰岛素原的内质网过度加工同样会导致内质网应激和β细胞功能障碍，这表明了一种由天然内源性蛋白质过度加工诱导的蛋白质病的普遍机制，发挥着关键的病理生理作用，并延伸到神经精神疾病。
Reduced somatostatin (SST) and dysfunction of SST-positive (SST+) neurons are hallmarks of neurological disorders and associated with mood disturbances, but the molecular origin of SST+ neuron vulnerability is unknown. Using chronic psychosocial stress as a paradigm to induce elevated behavioral emotionality in rodents, we report a selective vulnerability of SST+ neurons through exacerbated unfolded protein response (UPR) of the endoplasmic reticulum (ER), or ER stress, in the prefrontal cortex. We next show that genetically suppressing ER stress in SST+ neurons, but not in pyramidal neurons, normalized behavioral emotionality induced by psychosocial stress. In search for intrinsic factors mediating SST+ neuron vulnerability, we found that the forced expression of the SST precursor protein (preproSST) in SST+ neurons, mimicking psychosocial stress-induced early proteomic changes, induces ER stress, whereas mature SST or processing-incompetent preproSST does not. Biochemical analyses further show that psychosocial stress induces SST protein aggregation under elevated ER stress conditions. These results demonstrate that SST processing in the ER is a SST+ neuron-intrinsic vulnerability factor under conditions of sustained or over-activated UPR, hence negatively impacting SST+ neuron functions. Combined with observations in major medical illness, such as diabetes, where excess ER processing of preproinsulin similarly causes ER stress and β cell dysfunction, this suggests a universal mechanism for proteinopathy that is induced by excess processing of native endogenous proteins, playing critical pathophysiological roles that extend to neuropsychiatric disorders.
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DOI：
10.1126/science.1173155
发表时间：
2009-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maji SK;Perrin MH;Sawaya MR;Jessberger S;Vadodaria K;Rissman RA;Singru PS;Nilsson KP;Simon R;Schubert D;Eisenberg D;Rivier J;Sawchenko P;Vale W;Riek R
通讯作者：
Riek R
生长抑素，神经元脆弱性和行为情绪。
影响因子：
11
作者：
Lin, L. C.;Sibille, E.
通讯作者：
Sibille, E.
影响因子：
17.7
作者：
Nucifora, Leslie G.;MacDonald, Matthew L.;Nucifora, Frederick C., Jr.
通讯作者：
Nucifora, Frederick C., Jr.
影响因子：
2
作者：
Arancibia, S;Rage, F;Armario, A
通讯作者：
Armario, A
影响因子：
11
作者：
Bradshaw, Nicholas J.;Korth, Carsten
通讯作者：
Korth, Carsten