Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson’s disease, negatively affecting patient’s functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson’s disease are still elusive, limiting treatment and prevention strategies. This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous mutations in GBA1, the strongest risk gene for Parkinson’s disease that encodes glucocerebrosidase (GCase), a lysosome enzyme that degrades the glycosphingolipid glucosylceramide into glucose and ceramide. Using a Gba1L444P/+ mouse model, we provide evidence that L444P heterozygous Gba1 mutation (L444P/+) causes hippocampus-dependent spatial and reference memory deficits independently of α-synuclein (αSyn) accumulation, GCase lipid substrate accumulation, dopaminergic dysfunction and motor deficits. The mutation disrupts hippocampal synaptic plasticity and basal synaptic transmission by reducing the density of hippocampal CA3-CA1 synapses, a mechanism that is dissociated from αSyn-mediated presynaptic neurotransmitter release. Using a well-characterized Thy1-αSyn pre-manifest Parkinson’s disease mouse model overexpressing wild type human αSyn, we find that the L444P/+ mutation exacerbates hippocampal synaptic αSyn accumulation, synaptic and cognitive impairment in young Gba1L444P/+:Thy1-αSyn double mutant animals. With age, Thy1-αSyn mice manifest motor symptoms, and the double mutant mice exhibit more exacerbated synaptic and motor impairment than the Thy1-αSyn mice. Taken together, our results suggest that heterozygous L444P GBA1 mutation alone perturbs hippocampal synaptic structure and function, imposing a subclinical pathological burden for cognitive impairment. When co-existing αSyn overexpression is present, heterozygous L444P GBA1 mutation interacts with αSyn pathology to accelerate Parkinson’s disease-related cognitive impairment and motor symptoms.

中文翻译：

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与 L444P 杂合葡萄糖脑苷脂酶突变相关的突触和认知障碍


认知障碍是帕金森病的一个常见但知之甚少的非运动方面，对患者的功能能力和生活质量产生负面影响。帕金森病认知障碍的潜在机制仍然难以捉摸，限制了治疗和预防策略。本研究调查了与 GBA1 杂合突变相关的认知障碍的分子和细胞基础，GBA1 是帕金森病最强的风险基因，编码葡萄糖脑苷脂酶 （GCase），GCase 是一种将鞘糖脂葡萄糖神经酰胺降解为葡萄糖和神经酰胺的溶酶体酶。使用 Gba1L444P/+ 小鼠模型，我们提供证据表明 L444P 杂合 Gba1 突变 （L444P/+） 导致海马依赖性空间和参考记忆缺陷，与α-突触核蛋白 （αSyn） 积累、GCase 脂质底物积累、多巴胺能功能障碍和运动缺陷无关。该突变通过降低海马 CA3-CA1 突触的密度来破坏海马突触可塑性和基底突触传递，这种机制与 αSyn 介导的突触前神经递质释放分离。使用过表达野生型人 αSyn 的表征良好的 Thy1-αSyn 前显帕金森病小鼠模型，我们发现 L444P/+ 突变加剧了年轻 Gba1L444P/+：Thy1-αSyn 双突变动物的海马突触 αSyn 积累、突触和认知障碍。随着年龄的增长，Thy1-αSyn 小鼠表现出运动症状，并且双突变小鼠比 Thy1-αSyn 小鼠表现出更严重的突触和运动障碍。 综上所述，我们的结果表明，杂合子 L444P GBA1 突变单独扰乱了海马突触结构和功能，给认知障碍带来了亚临床病理负担。当存在共存的 αSyn 过表达时，杂合子 L444P GBA1 突变与 αSyn 病理相互作用，加速帕金森病相关的认知障碍和运动症状。