CINAC, Hospital Universitario HM Puerta del Sur, Móstoles, Universidad CEU-San Pablo, Madrid, Spain; Hospital Nacional de Parapléjicos, Toledo, Spain.
CINAC, Hospital Universitario HM Puerta del Sur, Móstoles, Universidad CEU-San Pablo, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Neuron. 2018 Sep 19;99(6):1116-1128. doi: 10.1016/j.neuron.2018.07.028.
In Parkinson's disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset. Since a defined somatotopic arrangement in the SNc has not been recognized, this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression (Braak's hypothesis, prionopathy). Here we propose that corticostriatal activity may represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson's disease. As a pathogenic mechanism, corticostriatal activity may promote secretion of striatal extracellular alpha-synuclein, favoring its pathological aggregation at vulnerable dopaminergic synapses. A similar pathogenic process may occur at corticofugal projections to the medulla oblongata and other vulnerable structures, thereby contributing to the bottom-up progression of Lewy pathology. This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson's disease.
在帕金森病中，黑质致密部（SNc）中的黑质纹状体多巴胺能神经元进行性神经退行性变与典型的运动特征相关，这些运动特征通常具有局灶性发作。由于尚未认识到 SNc 中明确的躯体定位排列，因此这种局灶性运动发作无法用目前的疾病进展的自上而下的发病理论（Braak 假说、朊病毒病）来解释。在这里，我们提出皮质纹状体活动可能代表黑质纹状体终末的关键躯体定位“应激源”，最终导致逆行黑质纹状体变性，并导致帕金森病的局灶性运动发作和进展。作为一种发病机制，皮质纹状体活动可能促进纹状体外源性α-突触核蛋白的分泌，有利于其在易受影响的多巴胺能突触病理性聚集。类似的发病过程可能发生在皮质投射到延髓和其他脆弱结构的投射中，从而有助于 Lewy 病理的自上而下进展。这种皮质发病机制可能与自下而上的机制共存，为寻找影响帕金森病发病和进展中多巴胺能细胞易感性的因素提供了一个整合的自上而下的视角。
