Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Mov Disord. 2021 Mar;36(3):716-728. doi: 10.1002/mds.28383. Epub 2020 Nov 17.
Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α-synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process.
We sought to dissect the underlying neurobiology of novelty-induced hyperactivity, reminiscent of psychosis-like behavior, in human α-synuclein BAC rats.
Herein, we demonstrate a prodromal psychosis-like phenotype, including late-onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty-induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d-amphetamine and reversed by classical and atypical antipsychotics. MicroRNA-mediated α-synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age-, brain region- and gene dose-dependent aberrant α-synuclein, including hyperphosphorylation, C-terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%).
Our findings demonstrate a potential role of α-synuclein in Parkinson's disease psychosis and provide evidence of region-specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized. © 2020 International Parkinson and Movement Disorder Society.
帕金森病精神病是一种普遍但未被报告和研究不足的帕金森病非运动表现，也是最具致残性的表现。目前尚不清楚α-突触核蛋白是否在精神病中起作用，如果是这样，这种内表型可能对阐明神经退行性过程至关重要。
我们试图剖析人类α-突触核蛋白 BAC 大鼠新奇诱导过度活跃的潜在神经生物学机制，这类似于精神病样行为。
在此，我们展示了一种前驱精神病样表型，包括迟发性感觉运动门控障碍、纹状体多巴胺能信号过度活跃以及持续的新奇诱导过度活跃（长达 18 个月），尽管基础运动活动减少，但被安非他命增强，并被经典和非典型抗精神病药逆转。腹侧中脑的 microRNA 介导的α-突触核蛋白下调可挽救过度活跃的表型并恢复纹状体多巴胺水平。这种表型伴随着与年龄、脑区和基因剂量相关的大量异常α-突触核蛋白，包括过度磷酸化、C 端截断、聚集病理学和轻度黑质神经退行性变（27%）。
我们的研究结果表明α-突触核蛋白在帕金森病精神病中可能起作用，并为神经退行性前的特定区域干扰提供了证据。报道的表型与最新的临床发现一致，提示可能存在前运动性高多巴胺状态，同时前运动性精神病症状也越来越被认识到。
