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Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons

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NEUROBIOLOGY OF DISEASE 2000年第4期7卷 274-285页

作者： Dupuis, L de Tapia, M René, F Lutz-Bucher, B Gordon, JW Mercken, L Pradier, L Loeffler, JP Inst Physiol & Chim Biol UMR CNRS 7519 Lab Neurophysiol Cellulaire & Integree F-67084 Strasbourg France Mt Sinai Med Ctr Dept Obstet Gynecol New York NY 10029 USA Aventis Cent Nervous Syst Dept F-94403 Vitry France

In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology. (C) 2000 Academic Press.

关键词：肌萎缩侧索硬化/代谢肌萎缩侧索硬化/病理学轴突运输/生理学疾病模型动物组蛋白类/代谢驱动蛋白/代谢小鼠转基因运动神经元/代谢运动神经元/病理学突变误义神经变性/代谢原虫蛋白质类/代谢 RNA 信使/代谢序列分析 DNA 脊髓/代谢超氧化物歧化酶/遗传学超氧化物歧化酶/代谢增量调节动物小鼠

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Differential expression of group I metabotropic glutamate receptors in rat spinal cord somatic and autonomic motoneurons:: Possible implications for the pathogenesis of amyotrophic lateral sclerosis

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NEUROBIOLOGY OF DISEASE 1999年第2期6卷 140-147页

作者： Anneser, JMH Borasio, GD Berthele, A Zieglgänsberger, W Tölle, TR Univ Munich Klinikum Grosshadern Dept Neurol D-81377 Munich Germany Max Planck Inst Psychiat D-80804 Munich Germany Tech Univ Munich Dept Neurol D-81675 Munich Germany

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of somatic, but not autonomic, motoneurons. The reason for this selective vulnerability is unknown. The pathogenesis of ALS is thought to involve glutamatergic excitotoxic mechanisms. While overactivation of ionotropic glutamate receptors may trigger excitotoxicity, we have previously shown that stimulation of group I metabotropic glutamate receptors (mGluRs) can exert neuroprotective effects on cultured motoneurons. Using in situ hybridization, we found a differential expression of group I mGluRs (mGluR1 and 5) in rat spinal cord. Autonomic motoneurons from the sacral parasympathetic Onuf's nucleus and thoracic sympathetic neurons, which are spared in ALS, express high levels of mGluR5, while somatic motoneurons do not. In addition, mGluR1 mRNA is found only in smaller somatic motoneurons, which seem to be less vulnerable in ALS. Thus, differential mGluR expression might provide a possible clue to the selective vulnerability of different motoneuronal subpopulations in ALS. (C) 1999 Academic Press.

关键词：肌萎缩侧索硬化/代谢肌萎缩侧索硬化/病理学自主神经系统/代谢自主神经系统/超微结构细胞大小图像处理计算机辅助原位杂交运动神经元/代谢运动神经元/超微结构大鼠 Wistar 受体亲代谢性谷氨酸盐/生物合成受体亲代谢性谷氨酸盐/代谢脊髓/代谢脊髓/超微结构动物女(雌)性大鼠

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Alteration of the Bcl-x/Bax ratio in a transgenic mouse model of amyotrophic lateral sclerosis:: Evidence for the implication of the p53 signaling pathway

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NEUROBIOLOGY OF DISEASE 2000年第4期7卷 406-415页

作者： de Aguilar, JLG Gordon, JW René, F de Tapia, M Lutz-Bucher, B Gaiddon, C Loeffler, JP Univ Strasbourg 1 UMR CNRS 7519 Lab Neurophysiol Cellulaire & Integree F-67084 Strasbourg France Mt Sinai Med Ctr Dept Obstet Gynecol New York NY 10029 USA

Molecular mechanisms promoting neuronal death in amyotrophic lateral sclerosis (ALS) were investigated using transgenic mice that overexpressed the G86R mutated form of the Cu/Zn superoxide dismutase (SOD1) gene. We observed: (i) alteration of the Bcl-x/Bax ratio and (ii) activation of the transcription factor p53, as deduced from its location within neuron nuclei. We further demonstrated that ectopic expression of the G86R mutant SOD1 in PC12 cells enhanced both p53 expression and phosphorylation, leading to transcriptional stimulation of p53-responsive genes. These findings provide evidence that the p53 signaling pathway is activated in SOD1-linked familial ALS and may play a causative role in spinal cord neuron apoptosis by modulating the Bcl-x/Bax ratio, (C) 2000 Academic Press.

关键词：肌萎缩侧索硬化/代谢疾病模型动物腰骶部小鼠转基因突变误义原癌基因蛋白质类/代谢原癌基因蛋白质c-bcl-2/代谢信号传导/生理学脊髓/代谢超氧化物歧化酶/遗传学超氧化物歧化酶/代谢肿瘤抑制蛋白质p53/代谢 bcl-2相关X蛋白质 bcl-X蛋白质动物男(雄)性小鼠

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Calcium dynamics and buffering in oculomotor neurones from mouse that are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motoneurone disease

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第2期525卷 433-445页

作者： Vanselow, BK Keller, BU Univ Gottingen Zentrum Physiol & Pathophysiol D-37073 Gottingen Germany

1. Motoneurones are particularly vulnerable both in human forms of amyotrophic lateral sclerosis (ALS) and corresponding animal models of the disease. While most motoneurone populations are selectively impaired, oculomotor neurones are essentially resistant to ALS-related damage. 2. Motoneurone vulnerability has been closely linked to disruptions of calcium signalling. To investigate underlying events, we performed a quantitative analysis of calcium homeostasis in oculomotor neurones from mice by simultaneous patch-clamp recordings in sliced tissue and microfluorometric-calcium measurements. 3. Somatic calcium dynamics were investigated by using a computer-controlled microfluorometric system. In oculomotor neurones, basal calcium concentrations were around 80 nM and depolarisation-induced calcium responses were observed for membrane voltages positive to -40 mV. 4. Endogenous calcium homeostasis was quantified by using the 'added buffer' approach. The recovery phase of depolarisation-induced calcium transients was well approximated by a mono-exponential function with a decay time constant that showed a linear dependence on dye concentration. The extrapolated time constant in the absence of indicator dye was 1.7 +/- 0.2 s (n = 11 cells, 21 degrees C). 5. Endogenous calcium binding ratios (kappa(s)) were found to be 264 +/- 25 (n = 11 cells), indicating that 99.6% of cytosolic calcium ions were taken up by endogenous buffers. Recovery of calcium transients was characterised by an 'effective' extrusion rate gamma = 156 +/- 20 s(-1) (n = 11 cells, 21 degrees C). 6. Endogenous calcium binding ratios in oculomotor neurones were 5- to 6-fold larger compared with those of more vulnerable motoneurones in the nucleus hypoglossus and spinal cord. In a first order approximation, they reduced the volume of local calcium elevations around open calcium channels, lowered peak amplitudes of global calcium transients for a given influx and prolonged calcium recovery times for a given

关键词：肌萎缩侧索硬化/代谢缓冲剂钙信号疾病模型动物荧光染料 Fura-2 内环境稳定动力学膜电位模型神经学运动神经元病/代谢神经变性/代谢神经元/代谢动眼神经/细胞学动眼神经/代谢膜片钳术动物人类小鼠

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Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis

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AMERICAN JOURNAL OF PATHOLOGY 2003年第2期163卷 609-619页

作者： Hishikawa, N Niwa, J Doyu, M Ito, T Ishigaki, S Hashizume, Y Sobue, G Nagoya Univ Grad Sch Med Dept Neurol Nagoya Aichi 4668550 Japan Aichi Med Univ Dept Neuropathol Inst Med Sci Aging Aichi Japan

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of a-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.

关键词：肌萎缩侧索硬化/代谢肌萎缩侧索硬化/病理学抗体/代谢细胞系 DNA结合蛋白质类/代谢包涵体/代谢 Lewy体病/代谢 Lewy体病/病理学分子量多系统萎缩/代谢多系统萎缩/病理学神经组织蛋白质类/代谢神经胶质/代谢神经胶质/超微结构神经元/代谢神经元/超微结构帕金森病/代谢帕金森病/病理学蛋白质结合超氧化物歧化酶/代谢突触核蛋白类泛素/代谢泛素蛋白连接酶类 α突触核蛋白老年人女(雌)性人类男(雄)性中年人

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EXCITATORY AMINO-ACID RECEPTORS IN HUMAN SPINAL-CORD - EVALUATION IN AMYOTROPHIC-LATERAL-SCLEROSIS PATIENTS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期648卷 260-262页

作者： ALLAOUA, H CHAUDIEU, I BOKSA, P PERRY, TL KRIEGER, C QUIRION, R FAC MED VANCOUVER VANCOUVER V6T 1W5BCCANADA MCGILL UNIV DEPT PSYCHIATVERDUN H4H 1R3QUEBECCANADA

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