A neuron‐specific <i>Isca1</i> knockout rat developments multiple mitochondrial dysfunction syndromes

Sheng, Hanxuan; Lu, Dongfang; Qi, Xiaolong; Ling, Yahao; Li, Jing; Zhang, Xu; Dong, Wei; Chen, Wei; Gao, Shan; Gao, Xiang; Zhang, Li; Zhang, Lianfeng

doi:10.1002/ame2.12318

Cited by 4 publications

(1 citation statement)

References 42 publications

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“…The loss or depletion of Nissl bodies indicates disruption in neuronal protein synthesis and overall cellular health. This is often associated with neuronal degeneration [ 25 ], dysfunction [ 26 ], or death [ 27 ]. Consistent with previous studies, our results showed a reduction in Nissl bodies in the arsenic-exposed groups, as indicated by the lighter Nissl staining.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing

Chu,

Lu,

Jiao

et al. 2023

Toxics

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Arsenic is a natural toxin which is widely distributed in the environment, incurring diverse toxicities and health problems. Previous studies have shown that long non-coding RNAs (LncRNAs) are also reported to contribute to As-induced adverse effects. LncRNAs are involved in the development of nerve injury, generally acting as sponges for microRNAs (miRNAs). This study aimed to investigate the competitive endogenous RNA (ceRNA) regulatory networks associated with arsenic-induced nerve damage. A total of 40 male Wistar rats were exposed to different doses of arsenic for 12 weeks, and samples were collected for pathological observation and high-throughput sequencing. The ceRNA network was constructed using Cytoscape, and key genes were identified through the PPI network and CytoHubba methods. A real-time quantitative PCR assay was performed to validate gene expression levels. The results showed that subchronic exposure to arsenic in drinking water resulted in pathological and ultrastructural damage to the hippocampal tissue, including changes in neuron morphology, mitochondria, and synapses. Exposure to arsenic results in the dysregulation of LncRNA and mRNA expression in the hippocampal tissues of rats. These molecules participated in multiple ceRNA axes and formed a network of ceRNAs associated with nerve injury. This study also verified key molecules within the ceRNA network and provided preliminary evidence implicating the ENRNOT-00000022622-miR-206-3p-Bdnf axis in the mechanism of neural damage induced by arsenic in rats. These findings provide novel insights into the underlying mechanism of nervous system damage induced by arsenic exposure.

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Section: Discussionmentioning

confidence: 99%

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing

Chu,

Lu,

Jiao

et al. 2023

Toxics

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A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Sheng

et al. 2023

Anim Models and Exp Med

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Background Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. Methods We generated neuron‐specific Isca1 knockout rat (Isca1flox/flox ‐NeuN‐Cre) using CRISPR‐Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. Results This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. Conclusions This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

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C1ql3knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats

Zhang,

Dong,

et al. 2024

Anim Models and Exp Med

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BackgroundC1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons. However, its function is still not clear. We established C1ql3‐deficient rats to investigate the role of C1QL3 in the brain.MethodsC1ql3 knockout (KO) rats were generated using CRISPR/Cas9. C1ql3 KO was determined by polymerase chain reaction (PCR), DNA sequencing, and western blotting. Microglia morphology and cytokine expression with or without lipopolysaccharide (LPS) stimulus were analyzed using immunohistochemistry and real‐time PCR. The brain structure changes in KO rats were examined using magnetic resonance imaging. Neuronal architecture alteration was analyzed by performing Golgi staining. Behavior was evaluated using the open field test, Morris water maze test, and Y maze test.ResultsC1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia, whereas C1ql3 KO did not influence the expression of pro‐inflammatory factors and anti‐inflammatory factors except IL‐10. C1ql3 KO brains had more amoeboid microglia types and higher Arg‐1 expression compared with the WT rats after LPS stimulation. The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats. C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density. C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory.ConclusionsC1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation, resulting in hyperactive behavior and impaired short memory in rats, which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.

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A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Cited by 4 publications

References 42 publications

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing

A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

C1ql3knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats

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