Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling

Zhu, Jie; Zou, Ming; Li, Yi Fei; Chen, Wen Jin; Liu, Ji Chuan; Chen, Hong; Fang, Li Pao; Zhang, Yan; Wang, Zhao Tao; Chen, Ji Bo; Huang, Wenhui; Shen, Li; Jia, Wei; Wang, Qin Qin; Zhen, Xuechu; Liu, Chun‐Feng; Shao, Li; Xiao, Zhi‐Cheng; Xu, Guangwu; Schwamborn, Jens Christian; Schachner, Melitta; Xu, Ru Xiang

doi:10.1093/cercor/bhz306

Cited by 33 publications

(41 citation statements)

References 59 publications

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“…VPA is commonly used as an antiepileptic drug. Clinical studies have shown that exposure to VPA in utero is associated with cognitive deficits, birth defects, and an increased risk of ASD [85] . Clinical evidence shows that there is a link between VPA exposure and both cognitive abnormalities and autism.…”

Section: Vpa Modelsmentioning

confidence: 99%

Animal models of autism: a perspective from autophagy mechanisms

Dana¹,

Tahtasakal²,

Şener³

2020

jtgg

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Autism spectrum disorder (ASD) is characterized by impairments in social interaction and the presence of stereotypy and restrictive behavior. The clinical heterogeneity of ASD makes it difficult to explain the mechanisms underlying the disease. In recent years, the association between autophagy and neuropsychiatric diseases has been investigated. In this review, we aimed elucidate the relationship between autism and autophagy mechanism in well-known autism relevant animal models. Autophagy is a cell-protective mechanism that allows cell survival in low nutrient conditions, often through the degradation of aging and damaged proteins and organelles. The target of rapamycin (TOR) complex is activated for the activation of autophagy. Apart from mTOR animal models, the valproic acid model is frequently used in autism studies. The coiled-coil and C2 domain containing 1A (CC2D1A) gene is one of the new candidate genes associated with ASD. In a recent study that used Cc2d1a knockout mice, microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin 1 expression levels were dysregulated in the hippocampus. It is thought that the impaired autophagy mechanism contributes to the etiology of ASD. These results showed that CC2D1A acts as a new biological pathway in autophagy. Choosing the right model is crucial for ASD studies, and further progress will be made as these results become available in the clinic. In particular, it is expected that further studies on CC2D1A will provide new information in this field.

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Section: Vpa Modelsmentioning

confidence: 99%

Animal models of autism: a perspective from autophagy mechanisms

Dana¹,

Tahtasakal²,

Şener³

2020

jtgg

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“…The resulting IgG fraction is further purified by absorption on the caspase 3 peptide (human) corresponding to the uncleaved caspase 3 site sequence (Sigma antibody datasheet). Using immunohistochemical techniques with this antibody, active caspase 3 has been detected in several mammalian species including rat (Benitez, Castro, Patterson, Muñoz, & Seltzere, 2014; Molina et al, 2020) and mouse (Zhu et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

Administration of 5‐bromo‐2′‐deoxyuridine interferes with neuroblast proliferation and promotes apoptotic cell death in the rat cerebellar neuroepithelium

Rodríguez-Vázquez

Martí

2020

J of Comparative Neurology

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The current study was conducted to assess whether a single administration of 5‐bromo‐2′‐deoxyuridine (BrdU) interferes with cell proliferation and leads to the activation of apoptotic cellular events in the prenatal cerebellum. BrdU effects across a wide range of doses (25–300 μg/g b.w.) were analyzed using immunohistochemical and ultrastructural procedures. The pregnant rats were injected with BrdU at embryonic day 13, and their fetuses were sacrificed from 5 to 35 hr after exposure. The quantification of several parameters such as the density of mitotic figures, and BrdU and proliferating cell nuclear antigen (PCNA)‐reactive cells showed that, in comparison with the saline injected rats, the administration of BrdU impairs the proliferative behavior of neuroepithelial cells. The above‐mentioned parameters were significantly reduced in rats injected with 100 μg/g b.w. of BrdU. The reduction was more evident using 200 μg/g b.w. The most severe effects were found with 300 μg/g b.w. of BrdU. The present findings also revealed that high doses of BrdU lead to the activation of apoptotic cellular events as evidenced by both terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay and immunohistochemistry for active caspase‐3. In comparison with saline rats, many apoptotic cells were found in rats injected with 100 μg/g b.w. of BrdU. The number of dying cells increased with 200 μg/g b.w. The most important number of apoptotic cells were observed in animals injected with 300 μg/g b.w. of BrdU. Ultrastructural studies confirmed the presence of neuroblasts at different stages of apoptosis.

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“…At the opposite side of the pathway, the pivotal kinase mTOR is a sensor of metabolic and nutrient stress regulating many cellular processes, including the repression of autophagy in normal conditions. Amongst the numerous E3 ligases that modulate mTOR signaling, two were investigated for autophagy readout: FBXW11 and TRIM32 maintain the repressive activity of mTOR on autophagy by degrading inhibitors of mTOR, respectively DEPTOR (Duan et al, 2011;Gao et al, 2011;Zhao et al, 2011) and RGS10 (Zhu et al, 2020). Directly under the control of mTOR, TFEB, a pivotal transcriptional regulator of autophagy genes is positively modulated by CHIP, which degrades preferentially its phosphorylated inactive forms and induces autophagy (Sha et al, 2017).…”

Section: Emerging Roles Of E3 Ligases In the Control Of Autophagymentioning

confidence: 99%

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Lescouzères

Bomont

2020

Front. Physiol.

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Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ∼800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

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Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling

Cited by 33 publications

References 59 publications

Animal models of autism: a perspective from autophagy mechanisms

Animal models of autism: a perspective from autophagy mechanisms

Administration of 5‐bromo‐2′‐deoxyuridine interferes with neuroblast proliferation and promotes apoptotic cell death in the rat cerebellar neuroepithelium

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

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