The Neuronal Cytoskeleton as a Potential Therapeutical Target in Neurodegenerative Diseases and Schizophrenia
The Neuronal Cytoskeleton as a Potential Therapeutical Target in Neurodegenerative Diseases and Schizophrenia
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DOI：
10.2174/1568007043336761
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发表时间：
2004-01-01
影响因子：
3
通讯作者：
Meza, I
中科院分区：
文献类型：
--
作者：
Benitez-King, G.;Ramirez-Rodriguez, G.;Meza, I
细胞骨架在维持神经元的高度不对称形状和结构极性方面起着关键作用，这对神经元生理学至关重要。细胞骨架重组在轴突发生中起着关键作用。在神经退行性疾病中，细胞骨架异常组装，神经传递受损。在阿尔茨海默病中，大量的淀粉样蛋白斑块和神经纤维缠结构成了大脑中存在的两种主要神经病理学改变。神经纤维缠结由几乎完全由微管相关蛋白tau组成的成对螺旋丝形成。在正常情况下，tau与微管结合，稳定神经元结构和完整性。tau蛋白的过度磷酸化被认为是成对螺旋丝形成的原因。神经退行性疾病中存在的细胞骨架异常的另一个例子是被认为是帕金森病的细胞病理学标志物的路易体。路易体由微管蛋白、MAP 1和MAP 2组成。神经元的形状，树突和棘的损失，以及神经元伸长的不规则分布发生在精神分裂症患者的特定脑区。海马非磷酸化的MAP 2和MAP 1B的增加被认为是精神分裂症中发现的躯体树突和细胞结构异常的原因。此外，接受抗精神病药物治疗的精神分裂症患者中神经元缠结更常见。累积的证据表明，神经退行性疾病和精神疾病与神经元中的细胞骨架改变有关，而细胞骨架改变反过来又使突触连接和将传入的轴突信息传递到体树突结构域的能力变弱。我们将回顾证据支持神经细胞骨架被破坏的神经退行性疾病和一些精神疾病，因此可能是一个目标的药物治疗。此外，目前的数据表明，褪黑激素，由松果体分泌的激素，促进轴突通过细胞骨架重排，除了褪黑激素在神经退行性疾病的潜在治疗用途将进行讨论。
The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.