Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia.
Human Brain Tissue Bank & Laboratory, Semmelweis University, 1094 Budapest, Hungary.
Cells. 2023 Jul 13;12(14):1848. doi: 10.3390/cells12141848.
Disrupted proteostasis is an emerging area of research into major depressive disorder. Several proteins have been implicated as forming aggregates specifically in the brains of subsets of patients with psychiatric illnesses. These proteins include CRMP1, DISC1, NPAS3 and TRIOBP-1. It is unclear, however, whether these proteins normally aggregate together in the same individuals and, if so, whether each protein aggregates independently of each other ("parallel aggregation") or if the proteins physically interact and aggregate together ("co-aggregation").
Post mortem insular cortex samples from major depressive disorder and Alzheimer's disease patients, suicide victims and control individuals had their insoluble fractions isolated and tested by Western blotting to determine which of these proteins are insoluble and, therefore, likely to be aggregating. The ability of the proteins to co-aggregate (directly interact and form common aggregate structures) was tested by systematic pairwise expression of the proteins in SH-SY5Y neuroblastoma cells, which were then examined by immunofluorescent microscopy.
Many individuals displayed multiple insoluble proteins in the brain, although not enough to imply interaction between the proteins. Cell culture analysis revealed that only a few of the proteins analyzed can consistently co-aggregate with each other: DISC1 with each of CRMP1 and TRIOBP-1. DISC1 was able to induce aggregation of full length TRIOBP-1, but not individual domains of TRIOBP-1 when they were expressed individually.
While specific proteins are capable of co-aggregating, and appear to do so in the brains of individuals with mental illness and potentially also with suicidal tendency, it is more common for such proteins to aggregate in a parallel manner, through independent mechanisms. This information aids in understanding the distribution of protein aggregates among mental illness patients and is therefore important for any future diagnostic or therapeutic approaches based on this aspect of mental illness pathology.
蛋白质稳态紊乱是研究重度抑郁症的一个新兴领域。有几种蛋白质已被确定为特定在患有精神疾病的患者亚群的大脑中形成聚集体。这些蛋白质包括 CRMP1、DISC1、NPAS3 和 TRIOBP-1。然而，目前尚不清楚这些蛋白质是否通常在同一人群中聚集在一起，如果是这样，那么这些蛋白质是否彼此独立地聚集在一起（“平行聚集”），或者这些蛋白质是否物理相互作用并聚集在一起（“共聚集”）。
取自重度抑郁症和阿尔茨海默病患者、自杀者和对照个体的死后岛叶皮质样本，其不可溶性部分被分离出来，并通过 Western 印迹进行测试，以确定哪些蛋白质是不可溶的，因此可能正在聚集。通过在 SH-SY5Y 神经母细胞瘤细胞中系统地表达成对的蛋白质来测试蛋白质的共聚集（直接相互作用并形成共同的聚集结构）能力，然后通过免疫荧光显微镜检查。
许多个体的大脑中存在多种不可溶蛋白质，尽管这不足以暗示蛋白质之间的相互作用。细胞培养分析表明，在分析的蛋白质中，只有少数几种能够一致地相互共聚集：DISC1 与 CRMP1 和 TRIOBP-1 中的每一种。DISC1 能够诱导全长 TRIOBP-1 聚集，但不能诱导单独表达时的 TRIOBP-1 各结构域聚集。
虽然特定的蛋白质能够共聚集，并且似乎在患有精神疾病和潜在自杀倾向的个体的大脑中也是如此，但这些蛋白质更常见的是通过独立的机制以平行方式聚集。这些信息有助于了解蛋白质聚集体在精神疾病患者中的分布，因此对于任何基于精神疾病病理学这一方面的未来诊断或治疗方法都很重要。
