Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons. Using an established bTBI rat model, we evaluated the changes of α-synuclein and tyrosine hydroxylase (TH), known hallmarks of PD, and acrolein, a reactive aldehyde and marker of oxidative stress, with the aim of revealing key pathways leading to PD post-bTBI. Indicated in both animal models of PD and TBI, acrolein is likely a point of pathogenic convergence. Here we show that after a single mild bTBI, acrolein is elevated up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. Acrolein elevation is accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. We further show that acrolein can directly modify and oligomerize α-synuclein in vitro. Taken together, our data suggests acrolein likely plays an important role in inducing PD pathology following bTBI by encouraging α-synuclein aggregation. These results are expected to advance our understanding of the long-term post-bTBI pathological changes leading to the development of PD, and suggest intervention targets to curtail such pathology.

中文翻译：

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丙烯醛介导的α-突触核蛋白病理学参与轻度冲击波诱发的帕金森神经变性的早期损伤后发病机制。


爆炸引起的创伤性脑损伤 (bTBI) 的幸存者对帕金森病 (PD) 的易感性增加，其特征是 α-突触核蛋白聚集和黑质纹状体多巴胺能神经元进行性变性。使用已建立的 bTBI 大鼠模型，我们评估了 α-突触核蛋白和酪氨酸羟化酶 (TH)（PD 的已知标志）以及丙烯醛（一种反应性醛和氧化应激标记物）的变化，旨在揭示导致 PD 后的关键途径-bTBI。在 PD 和 TBI 动物模型中都表明，丙烯醛可能是致病聚合点。在这里，我们发现，在一次轻度 bTBI 后，丙烯醛在尿液和整个脑组织（特别是黑质和纹状体）中全身升高长达一周。丙烯醛升高伴随着同一大脑区域中α-突触核蛋白寡聚化、多巴胺能失调以及丙烯醛/α-突触核蛋白相互作用的增强。我们进一步表明丙烯醛可以在体外直接修饰和寡聚α-突触核蛋白。综上所述，我们的数据表明丙烯醛可能通过促进 α-突触核蛋白聚集，在 bTBI 后诱发 PD 病理中发挥重要作用。这些结果预计将增进我们对导致 PD 发展的 bTBI 后长期病理变化的理解，并提出减少此类病理的干预目标。