PLoS One. 2025 May 12;20(5):e0324473. doi: 10.1371/journal.pone.0324473. eCollection 2025.
Parkinson’s disease (PD) is a movement disorder associated with genetic and age related causes. Although autosomal recessive early onset PD linked to parkin mutations does not exhibit α-Synuclein accumulation, while autosomal dominant and sporadic PD manifest with α-Synuclein inclusions, loss of dopaminergic substantia nigra neurons is a common denominator in PD. Here we show that decreased parkin ubiquitination and loss of parkin stability impair interaction with Beclin-1 and alter α-Synuclein degradation, leading to death of dopaminergic neurons. Tyrosine kinase inhibition increases parkin ubiquitination and interaction with Beclin-1, promoting autophagic α-Synuclein clearance and nigral neuron survival. However, loss of parkin via deletion increases α-Synuclein in the blood compared to the brain, suggesting that functional parkin prevents α-Synuclein release into the blood. These studies demonstrate that parkin ubiquitination affects its protein stability and E3 ligase activity, possibly leading to α-Synuclein sequestration and subsequent clearance.
帕金森病（PD）是一种与遗传和年龄相关病因有关的运动障碍性疾病。虽然与parkin基因突变相关的常染色体隐性早发性帕金森病不表现出α-突触核蛋白的积累，而常染色体显性和散发性帕金森病则表现为α-突触核蛋白包涵体，但多巴胺能黑质神经元的丧失是帕金森病的一个共同特征。我们在此表明，parkin泛素化减少和parkin稳定性丧失会损害其与Beclin-1的相互作用，并改变α-突触核蛋白的降解，导致多巴胺能神经元死亡。酪氨酸激酶抑制增加parkin泛素化及其与Beclin-1的相互作用，促进自噬性α-突触核蛋白清除和黑质神经元存活。然而，与大脑相比，通过缺失导致的parkin丧失会增加血液中α-突触核蛋白的含量，这表明功能性parkin可防止α-突触核蛋白释放到血液中。这些研究表明，parkin泛素化会影响其蛋白质稳定性和E3连接酶活性，可能导致α-突触核蛋白的隔离及随后的清除。
