Narwal Sonia, Singh Amit, Tare Meghana
Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
Department of Biology, University of Dayton, Dayton, OH, United States.
Front Cell Neurosci. 2024 Jan 4;17:1295805. doi: 10.3389/fncel.2023.1295805. eCollection 2023.
One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein () protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, . Mutations in and result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of and , their interactions in dopaminergic neurons remain understudied. Here we employ model to study the effect of collective overexpression of along with the downregulation of in the dopaminergic neurons of the posterior brain. We found that overexpression of along with downregulation of causes a reduction in the number of dopaminergic neuronal clusters in the posterior region of the adult brain, which is manifested as progressive locomotor dysfunction. Overexpression of and downregulation of collectively results in altered mitochondrial morphology in a cluster-specific manner, only in a subset of dopaminergic neurons of the brain. Further, we found that overexpression causes transcriptional downregulation of . However, this downregulation is not further enhanced upon collective overexpression and downregulation. This suggests that the interactions of and may not be additive. Our study thus provides insights into a potential link between α and interactions. These interactions result in altered mitochondrial morphology in a cluster-specific manner for dopaminergic neurons over a time, thus unraveling the molecular interactions involved in the etiology of Parkinson's Disease.
帕金森病（PD）的一个标志是错误折叠的α-突触核蛋白（）聚集，导致多巴胺能神经元选择性死亡。另一种形式的帕金森病的特征是E3泛素连接酶功能丧失。和的突变导致线粒体形态受损，导致多巴胺能神经元丧失。尽管对和的个体影响进行了广泛研究，但它们在多巴胺能神经元中的相互作用仍未得到充分研究。在这里，我们采用模型来研究在后脑多巴胺能神经元中共同过表达以及下调的影响。我们发现，过表达以及下调会导致成年大脑后部多巴胺能神经元簇数量减少，表现为进行性运动功能障碍。过表达和下调共同导致线粒体形态以簇特异性方式改变，仅在大脑中一部分多巴胺能神经元中出现。此外，我们发现过表达会导致转录下调。然而，在共同过表达和下调时，这种下调不会进一步增强。这表明和的相互作用可能不是累加的。因此，我们的研究为α和相互作用之间的潜在联系提供了见解。这些相互作用随着时间的推移以簇特异性方式导致多巴胺能神经元线粒体形态改变，从而揭示了帕金森病病因学中涉及的分子相互作用。
