Merck Serono S.A., Geneva, Switzerland.
PLoS One. 2012;7(7):e40457. doi: 10.1371/journal.pone.0040457. Epub 2012 Jul 11.
Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related in vivo and in vitro models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.
多发性硬化症（MS）是一种神经炎症性疾病，其特征是髓鞘逐渐丧失，少突胶质细胞（OL）介导的髓鞘再生失败，特别是在疾病的进展阶段。对控制 OL 前体细胞分化的信号机制有了更深入的了解，可能会为 MS 的髓鞘再生找到新的治疗靶点。目前已知约有 100 种哺乳动物蛋白酪氨酸磷酸酶（PTPs），其中许多在健康和疾病中都参与信号转导。我们采用系统的基因组方法，评估了多发性硬化症尸检组织以及相关的体内和体外疾病模型中的 PTP 基因活性。这一努力导致鉴定出 Dusp15/VHY，这是一种先前被认为仅在睾丸中表达的 PTP，在 OL 分化和 MS 病变中受到转录调控。随后的 RNA 干扰研究表明，Dusp15/VHY 是 OL 分化的关键调节因子。最后，我们鉴定出 PDGFR-beta 和 SNX6 是新的和特异的 Dusp15 底物，这表明这种 PTP 可能通过何种方式对 OL 分化进行控制。
