Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080, USA.
J Neurosci Res. 2010 Dec;88(16):3508-19. doi: 10.1002/jnr.22506. Epub 2010 Oct 8.
Paraneoplastic Ma1 (PNMA1) is a member of a family of proteins involved in an autoimmune disorder called paraneoplastic neurological syndrome. Although it is widely expressed in brain, nothing is known about the function of PNMA1 in neurons. We find that PNMA1 expression is highest in the perinatal brain, a period during which developmentally regulated neuronal death occurs. PNMA1 expression increases in cerebellar granule neurons (CGNs) induced to die by low potassium (LK) and in cortical neurons following homocysteic acid (HCA) treament. Elevated PNMA1 expression is also observed in the degenerating striatum in two separate mouse models of Huntington's disease, the R6/2 transgenic model and the 3-nitropropionic acid-induced chemical model. Suppression of endogenous PNMA1 expression inhibits LK-induced neuronal apoptosis. Ectopic expression of PNMA1 promotes apoptosis even in medium containing high potassium, a condition that normally ensures survival of CGNs. Deletion of the N-terminal half of the PNMA1 protein abrogates its apoptotic activity, whereas deletion of the C-terminal half renders the protein more toxic. Within the N-terminal half, the ability to induce neuronal death depends on the presence of a BH3-like domain. In addition to being necessary for apoptosis, the BH3-like domain is necessary for self-association of PNMA1. Apoptosis by PNMA1 expression is inhibited by overexpression of Bcl2, suggesting that PNMA1-induced neuronal death may depend on the binding of a proapoptotic member of the Bcl2 family to the BH3 domain. Taken together, our results suggest that PNMA1 is a proapoptotic protein in neurons, elevated expression of which may contribute to neurodegenerative disorders.
副肿瘤 Ma1（PNMA1）是参与称为副肿瘤神经系统综合征的自身免疫性疾病的蛋白质家族的成员。尽管它在大脑中广泛表达，但尚不清楚 PNMA1 在神经元中的功能。我们发现 PNMA1 的表达在围产期大脑中最高，这是一个发生发育性调节的神经元死亡的时期。在低钾（LK）诱导的小脑颗粒神经元（CGN）和同型半胱氨酸（HCA）处理后的皮质神经元中，PNMA1 的表达增加。在两种不同的亨廷顿病小鼠模型中，R6/2 转基因模型和 3-硝基丙酸诱导的化学模型中，退化纹状体中也观察到升高的 PNMA1 表达。内源性 PNMA1 表达的抑制抑制 LK 诱导的神经元凋亡。PNMA1 的异位表达甚至在含有高钾的培养基中促进凋亡，高钾条件通常可确保 CGN 的存活。PNMA1 蛋白的 N 端一半的缺失消除了其凋亡活性，而 C 端一半的缺失使蛋白更具毒性。在 N 端一半内，诱导神经元死亡的能力取决于存在 BH3 样结构域。除了对于凋亡是必需的之外，BH3 样结构域对于 PNMA1 的自我缔合也是必需的。PNMA1 表达引起的细胞凋亡被 Bcl2 的过表达抑制，表明 PNMA1 诱导的神经元死亡可能取决于凋亡成员与 BH3 结构域的结合。总之，我们的结果表明，PNMA1 是神经元中的一种促凋亡蛋白，其表达水平升高可能导致神经退行性疾病。
