Evidence for central nervous system glial cell plasticity in phenylketonuria
Evidence for central nervous system glial cell plasticity in phenylketonuria
复制标题
DOI：
10.1097/00005072-199607000-00005
复制
发表时间：
1996-07-01
影响因子：
3.2
通讯作者：
Levy, HL
中科院分区：
文献类型：
--
作者：
Dyer, CA;Kendler, A;Levy, HL
苯丙酮尿症（PKU）是由苯丙氨酸羟化酶（PAH）基因突变引起的，导致PAH活性缺乏和血液中苯丙氨酸的积累。主要病理表现为中枢神经系统白色物质的髓鞘化和胶质增生。在PKU的遗传模型Pah（enu 2）小鼠中观察到类似的白色物质病理学。我们研究了这只小鼠，以检查PKU中这些神经病理学变化的基础，并确定髓鞘形成不足和神经胶质增生是否独立发生或相互关联。尽管PKU脑内的白色物质束是低髓鞘化的，但免疫染色和蛋白质印迹分析揭示这些束含有丰富量的髓鞘标记物，即髓鞘碱性蛋白（MBP）、2 '，3'-环核苷酸3 '磷酸水解酶和髓鞘/少突胶质细胞特异性蛋白（MOSP）。然而，Western blot分析也显示MBP亚型表达异常。通过用Triton X-100提取组织切片进行单个细胞的研究。提取了大部分MOSP，剩余的MOSP在双标记细胞中清晰可见，即MOSP沿着胶质细胞酸性蛋白（GFAP）细丝共定位。同时表达MBP和GFAP的细胞也在视束中被鉴定。MBP和GFAP特异性抗体的核糖探针双标记显示，大多数GFAP阳性细胞表达MBP mRNA。我们的体外研究检测了培养的野生型少突胶质细胞对苯丙氨酸升高4周（wk）的反应。在这些条件下，约50%的少突胶质细胞表达GFAP丝，并未能阐述膜片。星形胶质细胞的增殖似乎不是神经胶质细胞增生的来源，因为PKU脑中GFAP阳性细胞的细胞核没有增殖细胞核抗原的免疫染色。在正常小鼠脑切片中检测到双标记细胞;然而，发现PKU小鼠白色物质束包含的双标记细胞数量约为正常组织的两倍。两者合计，这些数据表明，髓鞘和nonmyelinating少突胶质细胞存在于正常的成年人大脑中，并在响应毒性因子，如苯丙氨酸升高，髓鞘少突胶质细胞采用nonmyelinating表型，表达GFAP。由于髓鞘形成的雪旺细胞和GFAP阳性的非髓鞘形成的雪旺细胞通常存在于成人外周神经中，并且髓鞘形成的雪旺细胞通过切换到GFAP阳性的非髓鞘形成细胞来对病理情况做出反应，因此少突胶质细胞和雪旺细胞可能比以前认为的更相似。
Phenylketonuria (PKU) is caused by mutation(s) in the phenylalanine hydroxylase (PAH) gene which lead to deficient PAH activity and an accumulation of phenylalanine in the blood. The primary pathologic finding is hypomyelination and gliosis of central nervous system white matter. Similar white matter pathology is observed in the Pah(enu2) mouse, a genetic model for PKU. We studied this mouse to examine the basis for these neuropathologic changes in PKU and to determine if hypomyelination and gliosis occur independently or are interrelated. Although white matter tracts within PKU brains are hypomyelinated, immunostaining and Western blot analyses revealed that these tracts contain abundant amounts of myelin markers, i.e. myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'phosphohydrolase, and myelin/oligodendrocyte-specific protein (MOSP). However, Western blot analyses also showed that MBP isoform expression was aberrant. Investigation of individual cells was performed by extraction of tissue sections with Triton X-100. Most of the MOSP was extracted, with the remaining MOSP clearly visible in dual labeled cells, i.e. MOSP was colocalized along glial fibrillary acidic protein (GFAP) filaments. Cells expressing both MBP and GFAP were also identified in optic tract. Double labeling with a riboprobe for MBP and antibodies specific for GFAP revealed that the majority of GFAP-positive cells expressed MBP mRNA. Our in vitro studies examined the response of cultured wild type oligodendrocytes to elevated phenylalanine for 4 weeks (wk). Under these conditions, about 50% of the oligodendrocytes expressed GFAP filaments and failed to elaborate membrane sheets. Proliferation of astrocytes appears not to be the source of gliosis, since the nuclei of GFAP-positive cells in the PKU brains did not immunostain for proliferating cell nuclear antigen. Dual-labeled cells were detected in normal mouse brain sections; however, PKU mouse white matter tracts were found to contain about twice the number of dual-labeled cells compared to normal tissue. Taken together, these data suggest that both myelinating and nonmyelinating oligodendrocytes are present in the normal adult brain, and that in response to a toxic factor such as elevated phenylalanine, myelinating oligodendrocytes adopt a nonmyelinating phenotype that expresses GFAP. Since myelinating Schwann cells and GFAP-positive nonmyelinating Schwann cells are normally present in adult peripheral nerve, and the myelinating Schwann cells react to pathologic situations by switching to GFAP-positive nonmyelinating cells, it may be that oligodendrocytes and Schwann cells are more similar than previously thought.