Does Sporadic Amyotrophic Lateral Sclerosis Spread Via Axonal Connectivities?
Does Sporadic Amyotrophic Lateral Sclerosis Spread Via Axonal Connectivities?
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DOI：
10.1055/s-0043-111405
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发表时间：
2017-08-01
影响因子：
--
通讯作者：
Del Tredici, K.
中科院分区：
文献类型：
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作者：
Braak, H.;Neumann, M.;Del Tredici, K.
散发性肌萎缩侧索硬化症（sALS）的病理过程与细胞质内含物的核蛋白（TDP-43）的形成有关，仅限于少数几种类型的长轴突投射神经元。初级运动新皮质的巨大贝茨锥体细胞以及下脑干和脊髓的大运动神经元很早就参与其中。在人脑中，这两种神经元类型在很大程度上通过单突触轴突投射相互连接。受影响的神经元的细胞核逐渐丧失其正常表达的蛋白质TDP-43。在运动神经元中，这种核丢失之后是在细胞质中形成不溶性TDP-43-免疫阳性内含物，而在贝茨细胞中，核表达的丢失持续了一段未知的时间，而不伴有体树突和/或轴浆聚集。可能在皮质锥体细胞（贝茨细胞）中，核清除最初导致形成异常但仍可溶的胞质TDP-43，其可进入轴质，并且在通过直接突触接触传递后，诱导受体神经元中新的TDP-43失调和聚集。在sALS过程中连续发展的传播模式的轨迹与主要是皮质投射神经元通过轴突运输通过直接突触接触导致在所涉及的皮质下区域的受体神经细胞内的含TDP-43的内含物的二次诱导的传播一致。
The pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large -motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these two neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In -motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induce anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions.