【神经科学前沿技术培训系列】详见文末
责编︱王思珍
值得注意的是,与PINK1缺失猴模型不同,Parkin缺失对猴大脑早期发育中神经细胞功能未见明显影响,这可能是由于PINK1作为上游激酶还参与调节其它重要底物。比如,该团队还利用新鲜野生型猴脑组织进行蔗糖密度梯度离心法分离不同亚细胞器,发现PINK1和Parkin蛋白在生理状态下的猴脑中具有不同的亚细胞定位(Liu et al,Neural Regen Res 2024),也提示PINK1、Parkin蛋白除了通过Parkin磷酸化发挥功能之外,可能还有各自独立的功能。
Aaron Gitler(教授 美国斯坦福大学遗传学系)
Dimitri Krainc (教授、主任 美国西北大学神经病学系)
By developing a parkin-deficient monkey model, this study fills a gap left by rodent models that failed to replicate human PD neurodegeneration. This model provides a more accurate system to study the progression of PD and to test therapeutic interventions.
The findings also shed light on the mechanistic role of parkin phosphorylation in the regulation of α-synuclein, adding evidence to the idea that loss of parkin function contributes to the neurodegenerative process. This mechanistic insight is critical for understanding how PD develops and progresses at the molecular level.
The study suggests that interventions aimed at restoring parkin phosphorylation could be a promising therapeutic strategy for mitigating α-synuclein accumulation and, by extension, the neurodegeneration observed in PD. This has significant implications for drug development aimed at halting or slowing PD progression.In summary, this paper makes a significant contribution by providing the first in vivo evidence linking parkin phosphorylation to age-dependent neurodegeneration in a primate model, offering new therapeutic targets for Parkinson’s disease.
(译文)通过开发一个Parkin缺失的猴子模型,该项研究填补了小鼠模型未能复制人类帕金森病神经退行性改变所留下的空白。该模型提供了一个更准确的系统来研究帕金森病的进展以及测试治疗干预措施。
研究结果还揭示了Parkin磷酸化在α-突触核蛋白调节中的机制作用,为Parkin功能缺失导致神经退行性病变提供了重要证据。这一机制性的新见解对于理解帕金森病在分子水平上的发展和进展至关重要。
研究表明,旨在恢复Parkin磷酸化的干预措施可能会成为减轻α-突触核蛋白积累的有前景的治疗策略,并能够进一步减缓帕金森病中观察到的神经退行性病变。这对旨在阻止或减缓帕金森病病程发展的药物开发具有重要意义。
总之,这篇论文在灵长类动物模型中观察到Parkin蛋白磷酸化与年龄依赖性神经退行性病变的关联,首次提供了在体的重要证据,也为帕金森病提供了新的治疗靶点。
David C. Rubinsztein(教授 英国剑桥大学医学研究院和英国痴呆研究院)
This paper from Weili Yang, Xiao-Jiang Li, and Shihua Li’s labs is a tour de force focused on knockouts of the ubiquitin ligase Parkin in monkeys. In humans, mutations of Parkin and its kinase PINK1 cause autosomal recessive forms of Parkinson’s disease. This paper raises a number of interesting and important issues for Parkinson’s disease research. It shows age-dependent effects of Parkin knockout – no obvious phenotypes are seen when Parkin is depleted in developing monkey brains but this results in neurodegeneration in adult brains, with suggestions of age-dependent effects. This strongly highlights the importance of considering ageing factors and processes in our studies of neurodegeneration. While loss of PINK1 in monkeys also causes neurodegeneration, this appears to act in developing brains, raising the possibility that the biologies of PINK1 and Parkin loss may not be identical – while this may because these are enzymes which will impact other substrates, this is interesting to see in a non-human primate. Parkinson’s disease manifests with dramatic cell death in the substantia nigra (SN) although there is also some cortical loss, which may account for cognitive signs. Interestingly, in this model, SN neurons were much more vulnerable to Parkin depletion. Perhaps their most interesting finding is that Parkin protects against the accumulation of alpha-synuclein in these models – the buildups of this protein are a hallmark of sporadic Parkinson’s disease and excess alpha-synuclein resulting from gene duplications is sufficient to cause PD. My impression from the literature was that maybe PINK1 and Parkin deficiencies were impacting neuronal health through mechanisms independent of alpha-synuclein – however, the elegant experiments in this study clearly show that these proteins are somehow connected. This, along with other key findings from this paper, provides new insights that will provide fuel for important follow-on experiments.
(译文)这篇来自杨伟莉、李晓江和李世华实验室的论文是一项杰出的研究,其重点关注猴子中表达泛素连接酶的Parkin基因的敲除。在人类中,Parkin及其激酶PINK1的突变会导致常染色体隐性遗传帕金森病。这篇论文提出了一些有趣且重要的科学问题,涉及帕金森病的研究。该论文表明,Parkin基因敲除具有年龄依赖性效应——在发育中的猴大脑中,当Parkin被敲低时没有明显的表型,但在成年大脑中则会导致神经退变,提示存在年龄依赖性效应。这强烈提示了研究神经退行性病变时考虑衰老因素的重要性。虽然猴中PINK1的缺失也会导致神经退变,但这似乎也在发育中的大脑中出现,提示PINK1和Parkin的生物学功能并不相同——可能是因为PINK1激酶也会磷酸化其他底物。而Parkin缺失在非人灵长类动物中造成的神经细胞死亡非常有趣,与帕金森病相似,在黑质中表现为显著的细胞死亡,而一些皮层神经细胞的损失可能解释了认知障碍症状。在这个模型中,黑质的神经元对Parkin缺失更为敏感。该研究最有趣的发现是,Parkin能够防止这些模型中α-突触核蛋白的积累——而这种蛋白质的积累是散发性帕金森病的标志,因为基因重复导致的过量α-突触核蛋白表达足以引发帕金森病。根据文献报道,我的印象是PINK1和Parkin缺乏可能通过与α-突触核蛋白无关的机制来影响神经元——然而,这项研究中的精妙实验清楚地表明,这些蛋白质在某种程度上是相互关联的。这些发现以及这篇论文中的其他关键发现,为后续重要实验提供了新的见解。
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1.Chen XS, Han R, Liu YT, Huang W, Wang Q, Xiong X, Zhang Y, Zhao JG, Li SH, Li XJ, Yang WL. Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation. Zool Res. 2024 Mar 18;45(2):242-252.
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