Gene therapy using AAV-neurturin (CERE-120) attenuates behavioral deficits and protects striatal neurons in models of Huntington's disease
Shilpa RamaswamyJodi L. McBrideRaymond T. BartusChristopher D. HerzogMehdi GasmiEugene P. BrandonLili ZhouEM Berry-KravisJeffrey H. Kordower
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Subependymal zone
Abstract Strong labeling of the cells in the subependymal layer was produced by stereotaxic injection of 5 μCi of 3 H‐thymidine into the left lateral ventricle of the brain of one and a quarter month old rats weighing about 100 gm. These animals were sacrificed by glutaraldehyde perfusion from two hours to 21 days later. Blocks of corpus callosum with adjacent subependymal and ependymal layers were excised from the injected and non‐injected sides, and embedded in Epon; 0.5 μ thick sections were radioautographed and stained with toluidine blue. In the subependymal region, on both injected and non‐injected sides, there was an immediate uptake of label by many cells followed by an increase and later a decrease in the percent cells labeled. In the corpus callosum while at first the percent labeling of glial cells was rather low, it did increase slowly with time and, after seven days, exceeded that in the subependymal region. These results were interpreted as indicating that cells arising in the subependymal layer had migrated into the corpus callosum. Up to four days after injection, most of the label in corpus callosum was present in immature‐looking cells resembling the cells of the subependymal layer and referred to as free subependymal cells. With time, the percent labeling decreased in these cells while increasing in some of the glial cells. A labeling peak was observed for light oligodendrocytes at four to seven days and for dark oligodendrocytes at 21 days, whereas labeling of medium shade oligodendrocytes occurred at intermediate times. The succession of labeling peaks indicated a sequence of development from free subependymal cells through light and medium shade to dark oligodendrocytes. Few astrocytes carried label at any time; those which did seemed to have arisen from the transformation of labeled free subependymal cells. Microglia were unlabeled at two hours, but their percent labeling was high at 4–14 days. While the labeling of other glial cells reflected their physiological behavior, the labeling of microglia was a consequence of the trauma produced by the injection 0f tracer into the ventricle. In conclusion, cells coming from the subependymal layer appear to migrate into the corpus callosum where, in 100 gm rats, many of them transform into oligodendrocytes and a few into astrocytes.
Subependymal zone
Ependyma
Ependymal Cell
Lateral ventricles
Neuroglia
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Subependymal zone
Caudate nucleus
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Potencies of brain cells to DNA synthesis and proliferation were studied in two weeks old and adult mice in the norm and after the brain mechanical injury. No labeled large and middle neurons were found in the brain of intact and operated animals both under the pulse 3H-thymidine incorporation and saturation of mice with 3H-thymidine during 36 hrs. The same types of brains cells were labeled both in intact and operated two weeks old and adult mice: glial cells, cells of the subependymal zone, cells of the dentate gyrus inner margin, and sometimes, cells having characteristics of microneurons. The number of glial cells in the temporal cortex of intact mice diminished with the age. Under the brain trauma, the proliferative reaction of glia was expressed in a similiar way both in two weeks old and adult mice. The index of labeled cells in the subependymal zone is the same in these two age groups. With the age the cellular mass of subependymal zone decreases, rather than proliferative tendencies of supependymal zone. The brain traumatization resulted in the increase of labeled subependymal cell only under the direct injury of subependymal zone.
Subependymal zone
Thymidine
Precursor cell
Neuroglia
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The goal of the study was to identify the subependymal microglial cells of the III ventricle of the rat brain and to determine their structural characteristics. The sections of the brain of intact Wistar (n = 3) and Sprague-Dawley (n = 3) male rats were studied using the methods of immunocytochemistry and confocal laser microscopy. Subependymal microglia of the III ventricle was found to be a constantly present cell population. Two types of subependymal microgliocytes were identified--spindle-like and basket cells. Their processes penetrate the ependymal layer and reach its surface, thus contacting the cerebrospinal fluid (CSF), which suggests a possible participation of these cells in the structure of CSF-brain barrier.
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Ependyma
Ependymal Cell
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Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD.
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The subependymal plate of the hypothalamus of the hamster has been studied in this work. Our observations with the electron microscope show that the basal surface of the ependymal cells in this area are situated directly over the astrocytic elements. Ultrastructural studies which indicate two types of glial cells in the subependymal plate contradicted by the results of the present investigation demonstrating one type of glial cells in the hypothalamic subependymal plate. This fact is interpreted as the final result of a glial differentiation in adult hamsters.
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Ependymal Cell
Ependyma
Basal (medicine)
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Chronic neurodegenerative diseases, such as prion diseases or Alzheimer's disease, are associated with progressive accumulation of host proteins which misfold and aggregate. Neurodegeneration is restricted to specific neuronal populations which show clear accumulation of misfolded proteins, whilst neighbouring neurons remain unaffected. Such data raise interesting questions about the vulnerability of specific neuronal populations to neurodegeneration and much research has concentrated only on the mechanisms of neurodegeneration in afflicted neuronal populations. An alternative, undervalued and almost completely unstudied question however is how and why neuronal populations are resilient to neurodegeneration. One potential answer is unaffected regions do not accumulate misfolded proteins, thus mechanisms of neurodegeneration do not become activated. In this perspectives, we discuss novel data from our laboratories which demonstrate that misfolded proteins do accumulate in regions of the brain which do not show evidence of neurodegeneration and further evidence that microglial responses may define the severity of neurodegeneration.
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转基因的动物模型关于年龄依赖者 neurodegenerative 疾病的致病揭示了大部分并且证明了是为揭开的一个有用工具治疗学的目标。亨廷顿的疾病是被一次 CAG 重复的扩大引起的描绘得好的 neurodegenerative 混乱，它在 huntingtin (HTT ) 的 N 终端区域导致一条 polyglutamine 道的扩大。类似的 CAG/glutamine 扩大也被发现引起八以一种年龄依赖者方式影响不同大脑区域的另外的 neurodegenerative 疾病。这 CAG/glutamine 扩大的鉴定导致了许多转基因的动物模型的产生。这些不同动物模型，转基因的老鼠广泛地被调查了，并且他们显示出在他们的各自的疾病看的类似的神经病理学和显型。年龄依赖者 neurodegeneration 的普通病理学的特点是在影响大脑区域由错误褶层蛋白质组成的总数或包括的形成；然而，公开或惹人注目的 neurodegeneration 和 apoptosis 没为年龄依赖者疾病在很转基因的老鼠模型被报导，包括 HD。由比较转基因的 HD 老鼠，猪，和猴子模型的神经病理学，我们发现变异的 HTT 比老鼠是对更大的动物有毒的更多，并且更大的动物也显示出没被转基因的老鼠模型揭开了的神经病理学。这评论将为分析 neurodegenerative 疾病的致病并且开发有效治疗讨论转基因的大动物模型的重要性。
Neuropathology
Huntingtin Protein
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Huntington’s disease results from a polyglutamine expansion in the N-terminal region of huntingtin (htt). This abnormality causes protein aggregation and leads to neurotoxicity. Despite its widespread expression in the brain and body, mutant htt causes selective neurodegeneration in Huntington’s disease patient brains. However, Huntington’s disease mouse models expressing mutant htt do not have obvious neurodegeneration despite significant neurological symptoms. Most Huntington’s disease mouse models display the accumulation of toxic N-terminal mutant htt fragments in both the nucleus and neuronal processes, suggesting that these subcellular sites are hotspots for the early neuropathology of Huntington’s disease. Intranuclear htt affects gene expression and may cause neuronal dysfunction. Mutant htt in neuronal processes affects axonal transport and induces degeneration, and these effects may be more relevant to the selective neurodegeneration in Huntington’s disease. Growing evidence has also suggested that mutant htt mediates multiple pathological pathways. This review discusses the early pathological changes identified in Huntington’s disease cellular and animal models. These changes may be the causes of neurode-generation.
Huntingtin Protein
Neuropathology
Neurotoxicity
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