Heimfarth Luana, da Silva Ferreira Fernanda, Pierozan Paula, Loureiro Samanta Oliveira, Mingori Moara Rodrigues, Moreira José Cláudio Fonseca, da Rocha João Batista Teixeira, Pessoa-Pureur Regina
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil.
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS, Brazil.
Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2510-2520. doi: 10.1016/j.bbagen.2016.07.023. Epub 2016 Jul 27.
Diphenylditelluride (PhTe)2 is a potent neurotoxin disrupting the homeostasis of the cytoskeleton.
Cultured astrocytes and neurons were incubated with (PhTe)2, receptor antagonists and enzyme inhibitors followed by measurement of the incorporation of [32P]orthophosphate into intermediate filaments (IFs).
(PhTe)2 caused hyperphosphorylation of glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits (NFL, NFM and NFH) from primary astrocytes and neurons, respectively. These mechanisms were mediated by N-methyl-d-aspartate (NMDA) receptors, L-type voltage-dependent calcium channels (L-VDCCs) as well as metabotropic glutamate receptors upstream of phospholipase C (PLC). Upregulated Ca(2+) influx activated protein kinase A (PKA) and protein kinase C (PKC) in astrocytes causing hyperphosphorylation of GFAP and vimentin. Hyperphosphorylated (IF) together with RhoA-activated stress fiber formation, disrupted the cytoskeleton leading to altered cell morphology. In neurons, the high intracellular Ca(2+) levels activated the MAPKs, Erk and p38MAPK, beyond PKA and PKC, provoking hyperphosphorylation of NFM, NFH and NFL.
Our findings support that intracellular Ca(2+) is one of the crucial signals that modulate the action of (PhTe)2 in isolated cortical astrocytes and neurons modulating the response of the cytoskeleton against the insult.
Cytoskeletal misregulation is associated with neurodegeneration. This compound could be a valuable tool to induce molecular changes similar to those found in different pathologies of the brain.
二苯基二碲化物（PhTe）2是一种强效神经毒素，可破坏细胞骨架的稳态。
将培养的星形胶质细胞和神经元与（PhTe）2、受体拮抗剂和酶抑制剂一起孵育，然后测量[32P]正磷酸盐掺入中间丝（IFs）的情况。
（PhTe）2分别导致原代星形胶质细胞和神经元中的胶质纤维酸性蛋白（GFAP）、波形蛋白和神经丝亚基（NFL、NFM和NFH）发生过度磷酸化。这些机制由N-甲基-D-天冬氨酸（NMDA）受体、L型电压依赖性钙通道（L-VDCCs）以及磷脂酶C（PLC）上游的代谢型谷氨酸受体介导。星形胶质细胞中上调的Ca(2+)内流激活蛋白激酶A（PKA）和蛋白激酶C（PKC），导致GFAP和波形蛋白过度磷酸化。过度磷酸化的（IF）与RhoA激活的应力纤维形成一起，破坏了细胞骨架，导致细胞形态改变。在神经元中，高细胞内Ca(2+)水平除了激活PKA和PKC外，还激活丝裂原活化蛋白激酶（MAPKs）、细胞外信号调节激酶（Erk）和p38丝裂原活化蛋白激酶（p38MAPK），引发NFM、NFH和NFL的过度磷酸化。
我们的研究结果支持细胞内Ca(2+)是调节（PhTe）2在分离的皮质星形胶质细胞和神经元中的作用的关键信号之一，调节细胞骨架对损伤的反应。
细胞骨架调节异常与神经退行性变有关。这种化合物可能是诱导类似于在不同脑疾病中发现的分子变化的有价值工具。
