The RE1-silencing transcription factor (REST) represses the expression of neuronal-specific genes in non-neuronal cells by recruiting histone deacetylases (HDACs) and other histone modifying and chromatin remodeling proteins to the DNA. REST regulation of the expression of neuronal genes is required for the orderly developmental transition from a neuroepithelial stem cell to a functional neuron. Here, we examined the expression and function of REST in neonatal rat oligodendrocyte precursor cells (OPCs). OPCs develop from the same neuroepithelial stem cells as neurons, can be reprogrammed to act as neural stem-like cells in vitro , and require HDAC-mediated gene repression to develop into mature oligodendrocytes. We show that OPCs express functional REST protein and that REST interacts with several neuronal-specific genes whose expression is repressed in OPCs. REST transcript and protein expression increased fourfold during the first 48 h of oligodendrocyte differentiation. During this differentiation, the expression of RE1 containing neuronal genes further decreased as the transcription of oligodendrocyte-specific genes was activated. Expression of a dominant-negative form of REST in OPCs prevented the cells from developing into mature MBP-positive oligodendrocytes. Rather, the cells began to develop a neuronal phenotype characterized by increased expression of neuronal proteins, transcription factors, and cell-type-specific marker antigens. REST overexpression promoted the development of O4-positive pre-oligodendrocytes from OPCs. Together, these results show that REST function is required for the differentiation of OPCs into oligodendrocytes. By regulating the expression of neuronal genes, REST may also regulate the phenotypic plasticity of OPCs.
Objective: Describe a unique presentation and neuroimaging for autoimmune GFAP meningoencephalomyelitis. Identify Infliximab as an effective steroid-sparing therapy. Background: A novel intracellular astrocyte IgG autoantibody against GFAP has recently been identified as a biomarker for an autoimmune meningoencephalomyelitis. Design/Methods: Case Report Results: A 25 year old African American man presents with 7 months of decline in mental state and generalized weakness. Prior to the onset of these symptoms he had an unintentional loss of 30kg due to persistent nausea, hiccups, and headache. He then developed generalized weakness along with gait instability, frequent falls, and tremor. He began to have audio-visual hallucinations and impairment of short-term memory. His symptoms have not improved on anti-psychotic medications. He can only intermittently follow single-step commands and has sparse speech. He has intact cranial nerves, sensation, and reflexes. He has a high-frequency essential tremor and generalized weakness. Neuroimaging reveals diffuse leptomeningeal thickening and enhancement to brain and spinal cord along with enhancement of nerve roots. CSF has elevated protein (233mg/dL), 5 oligoclonal bands, elevated ACE (6.3U/dL), and lymphocytic pleocytosis. CT chest is concerning for hilar lymphadenopathy. With concern for neurosarcoidosis, he is started on high-dose steroids; however subsequent lymph node biopsy is negative for granulomatous disease. His mental state modestly improves on steroids with a rapid improvement following addition of infliximab. His CSF studies subsequently test positive for GFAP auto-antibodies. Conclusions: This case demonstrates autoimmune subacute meningoencephalitis due to astrocytopathy with GFAP auto-antibodies. Neuroimaging shows both leptomeningeal and nerve root enhancement, and his clinical condition significantly improves with the initiation of anti-TNF-alpha therapy with infliximab. The mechanism by which infliximab treats GFAP meningoencephalitis is unknown. However recent brain immunohistopathology demonstrated an extensive involvement of CD4+, CD3+, and CD8+ T cells, as well as B cells, plasma cells, and macrophages. Disclosure: Dr. Rodriguez has nothing to disclose. Dr. Romero has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda and Genzyme.
