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Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

ABSTRACT: Neocortex expansion and folding are related to human intelligence and cognition, but the molecular and cellular mechanisms underlying cortical folding remain poorly understood. Here, we report that the human gene SERPINA3 is linked to gyrification. Specifically, the overexpression of SERPINA3 induced neocortical folding, increased the abundance of neurons, and improved cognitive abilities. Further, SERPINA3 promoted proliferation of the outer radial glia (oRG, also referred to as the basal radial glia) and increased the number of upper-layer neurons. The downstream target Glo1 was determined to be involved in SERPINA3-induced gyrification. Moreover, SERPINA3 increased the proliferation of oRG by binding to the Glo1 promoter. Assessment of behavior performance showed enhanced cognitive abilities in SERPINA3 knock-in mice. Our findings will enrich the understanding of neocortical expansion and gyrification and provide insights into possible treatments for intellectual disability and lissencephaly syndrome.

SUBMITTER: Zhao J

PROVIDER: S-EPMC9681744 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

Zhao Jinyue J Feng Chao C Wang Wenwen W Su Libo L Jiao Jianwei J

Cell discovery 20221122 1

Neocortex expansion and folding are related to human intelligence and cognition, but the molecular and cellular mechanisms underlying cortical folding remain poorly understood. Here, we report that the human gene SERPINA3 is linked to gyrification. Specifically, the overexpression of SERPINA3 induced neocortical folding, increased the abundance of neurons, and improved cognitive abilities. Further, SERPINA3 promoted proliferation of the outer radial glia (oRG, also referred to as the basal radia ...[more]

PMID: 36414636

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Project description:The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential.

Dataset Information

Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

Publications

Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

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