Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, USA.
Acta Neuropathol Commun. 2017 Jan 10;5(1):3. doi: 10.1186/s40478-016-0403-7.
Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.
神经病理学和遗传学研究发现，突触前蛋白α-突触核蛋白（aSyn）可能与包括帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩在内的多种突触核蛋白病的发病机制有关。有证据表明，与磷脂膜结合的 aSyn 构象体在易于聚集的状态下自组装，在 aSyn 神经毒性中发挥关键作用。因此，我们假设与脂相关的 aSyn 的蛋白结合伴侣可能会抑制膜表面有毒的 aSyn 寡聚物的形成。为了验证这一假说，我们对先前显示与膜结合的 aSyn 选择性相互作用的蛋白内磺素-α（ENSA）进行了研究，评估了其对两种家族性 aSyn 突变体 A30P 和 G51D 的膜诱导聚集和神经毒性的影响。结果发现，野生型 ENSA，但不是非 aSyn 结合的 S109E 变体，干扰了膜诱导的 aSyn 自组装、aSyn 介导的囊泡破坏和 aSyn 神经毒性。免疫印迹分析显示，与非疾病个体相比，突触核蛋白病患者的脑内 ENSA 表达下调。总的来说，这些结果表明，ENSA 可以通过在膜表面发挥明显的伴侣样活性来减轻膜结合的 aSyn 的神经毒性作用，而 ENSA 表达的降低可能导致突触核蛋白病中的 aSyn 神经病理学。更普遍的是，我们的研究结果表明，促进脂结合的、淀粉样蛋白的蛋白与其结合伴侣之间的相互作用是减轻多种蛋白错误折叠疾病细胞毒性的可行策略。
