Abstract:
Alterations in the dopamine catabolic pathway are known to contribute to the degeneration of nigrostriatal neurons in Parkinson\'s disease (PD). The progressive cellular buildup of the highly reactive intermediate 3,4-dihydroxyphenylacetaldehye (DOPAL) generates protein cross-linking, oligomerization of the PD-linked αSynuclein (αSyn) and imbalance in protein quality control. In this scenario, the autophagic cargo sequestome-1 (SQSTM1/p62) emerges as a target of DOPAL-dependent oligomerization and accumulation in cytosolic clusters. Although DOPAL-induced oxidative stress and activation of the Nrf2 pathway promote p62 expression, p62 oligomerization rather seems to be a consequence of direct DOPAL modification. DOPAL-induced p62 clusters are positive for ubiquitin and accumulate within lysosomal-related structures, likely affecting the autophagy-lysosomal functionality. Finally, p62 oligomerization and clustering is synergistically augmented by DOPAL-induced αSyn buildup. Hence, the substantial impact on p62 proteostasis caused by DOPAL appears of relevance for dopaminergic neurodegeneration, in which the progressive failure of degradative pathways and the deposition of proteins like αSyn, ubiquitin and p62 in inclusion bodies represent a major trait of PD pathology.
摘要:
已知多巴胺分解代谢途径的改变有助于帕金森病(PD)中黑质纹状体神经元的变性。高反应性中间体3,4-二羟基苯乙醛(DOPAL)的逐渐细胞积聚产生蛋白质交联,PD连接的α突触核蛋白(αSyn)的寡聚化和蛋白质质量控制中的不平衡。在这种情况下,自噬货物隔离组1(SQSTM1/p62)是DOPAL依赖性寡聚化和在细胞溶质簇中积累的靶标。尽管DOPAL诱导的氧化应激和Nrf2通路的激活促进p62表达,p62低聚似乎是直接DOPAL修饰的结果。DOPAL诱导的p62簇对泛素呈阳性,并在溶酶体相关结构中积累,可能影响自噬-溶酶体功能。最后,通过DOPAL诱导的αSyn积累,p62寡聚化和聚类得到协同增强。因此,由DOPAL引起的p62蛋白抑制的实质性影响似乎与多巴胺能神经变性有关,其中降解途径的逐渐失败和蛋白质如αSyn的沉积,包涵体中的泛素和p62代表PD病理学的主要特征。