Goebel-Goody Susan M, Lombroso Paul J
Yale University School of Medicine, New Haven, CT 06520, USA.
Results Probl Cell Differ. 2012;54:223-41. doi: 10.1007/978-3-642-21649-7_12.
A priority of fragile X syndrome (FXS) research is to determine the molecular mechanisms underlying the functional, behavioral, and structural deficits in humans and in the FXS mouse model. Given that metabotropic glutamate receptor (mGluR) long-term depression (LTD) is exaggerated in FXS mice, considerable effort has focused on proteins that regulate this form of synaptic plasticity. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase implicated as an "LTD protein" because it mediates AMPA receptor internalization during mGluR LTD. STEP also promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn, thereby opposing synaptic strengthening. We hypothesized that dysregulation of STEP may contribute to the pathophysiology of FXS. We review how STEP's expression and activity are regulated by dendritic protein synthesis, ubiquitination, proteolysis, and phosphorylation. We also discuss implications for STEP in FXS and other disorders, including Alzheimer's disease. As highlighted here, pharmacological interventions targeting STEP may prove successful for FXS.
脆性X综合征（FXS）研究的一个重点是确定人类以及FXS小鼠模型中功能、行为和结构缺陷背后的分子机制。鉴于代谢型谷氨酸受体（mGluR）长期抑制（LTD）在FXS小鼠中被夸大，大量研究致力于调控这种突触可塑性形式的蛋白质。纹状体富集蛋白酪氨酸磷酸酶（STEP）是一种脑特异性磷酸酶，因其在mGluR LTD期间介导AMPA受体内化而被视为一种“LTD蛋白”。STEP还促进NMDA受体的内吞作用，并使ERK1/2和Fyn失活，从而对抗突触增强。我们假设STEP的失调可能导致FXS的病理生理过程。我们综述了STEP的表达和活性如何受树突状蛋白合成、泛素化、蛋白水解和磷酸化的调控。我们还讨论了STEP在FXS和其他疾病（包括阿尔茨海默病）中的意义。如此处强调的，针对STEP的药物干预可能对FXS有效。
