Paulėkas Erlandas, Vanagas Tadas, Lagunavičius Saulius, Pajėdienė Evelina, Petrikonis Kęstutis, Rastenytė Daiva
Department of Neurology, Lithuanian University of Health Sciences Kaunas Clinics, LT-50161 Kaunas, Lithuania.
Biomedicines. 2024 Sep 18;12(9):2121. doi: 10.3390/biomedicines12092121.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson's disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn's pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future.
帕金森病（PD）是全球第二常见的神经退行性疾病；因此，自首次被描述以来，虽已取得显著进展，但关于其发病机制和难以捉摸的根本原因仍存在谜团。病理性α-突触核蛋白（αSyn）聚集体在全身广泛分布，引发了对病因的质疑，这促使人们提出了几种假说，其中最突出的是αSyn相关蛋白病。路易小体内αSyn蛋白的鉴定，以及将αSyn基因座重复、三倍体以及点突变与家族性帕金森病联系起来的遗传证据，都强调了αSyn在引发和传播全脑路易小体病理过程中的重要性。在单基因和散发性帕金森病中，早期炎症和突触功能障碍的存在会通过线粒体、溶酶体和内体功能损害导致αSyn聚集和神经元死亡。然而，关于αSyn发病机制仍有许多有待了解之处，这在很大程度上依赖于生物标志物和治疗策略。在本综述中，我们提供了新出现的证据，阐述了目前关于αSyn对帕金森病病理生理影响的认识，以及其作为特定疾病生物标志物或疾病修饰疗法主要靶点的可能作用，强调这种认识为近期疾病修饰疗法提供了最佳潜力。
