Current Articles

2025, Volume 52,  Issue 10

Review
Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review
Lamei Yuan, Yuewen Yang, Yi Guo, Hao Deng
2025, 52(10): 1155-1176. doi: 10.1016/j.jgg.2025.05.008
Abstract:
Amyotrophic lateral sclerosis (ALS), one of the most prevalent neurodegenerative disorders, is pathologically characterized by the progressive degeneration of both upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 2–4 years post-diagnosis. ALS is categorized into familial ALS (FALS) and sporadic ALS, with FALS accounting for approximately 10% of ALS cases. As a genetically heterogeneous disease, ALS exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked transmission, and genetic factors play pivotal roles in disease pathogenesis. To date, at least 34 disease-causing loci and 32 genes for ALS have been identified. The investigations of mutant protein products and the establishment of animal models have unraveled potential pathogenic pathways, offering insights into the mechanisms of neurodegeneration in ALS. This review focuses on ALS clinical characteristics, neuropathological features, causative loci/genes, genetic susceptibility factors, animal models, and pathogenic mechanisms, with particular attention to recent advances in genetic findings and pathogenic pathways of ALS. Elucidation of the genetic basis of ALS could provide the scientific foundation for personalized treatments to address this recalcitrant disease.
Postnatal critical-period brain plasticity and neurodevelopmental disorders: revisited circuit mechanisms
Ziwei Shang, Xiaohui Zhang
2025, 52(10): 1177-1188. doi: 10.1016/j.jgg.2025.07.006
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Critical periods (CPs) are defined as postnatal developmental windows during which brain circuits exhibit heightened sensitivity to altered experiences or sensory inputs, particularly during brain development in humans and animals. During the CP, experience-induced refinements of neural connections are crucial for establishing adaptive and mature brain functions, and aberrant CPs are often accompanied by many neurodevelopmental disorders (NDDs), including autism spectrum disorders and schizophrenia. Understanding neural mechanisms underlying the CP regulation is key to delineating the etiology of NDDs caused by abnormal postnatal neurodevelopment. Recent evidence from studies using innovative experimental tools has continuously revisited the inhibition-gating theory of CP to systematically elucidate the differential roles of distinct inhibitory circuits. Here, we provide a comprehensive review of classical experimental findings and emerging inhibitory-circuit regulation mechanisms of the CP, and further discuss how aberrant CP plasticity is associated with NDDs.
Original Research
Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome
Yan Huang, Zhenglong Xiang, Yaqin Xiang, Hu Pan, Mei He, Zhenming Guo, Oguz Kanca, Chen Liu, Zhao Zhang, Huaizhe Zhan, Yuan Wang, Qing-Ran Bai, Hugo J. Bellen, Hua Wang, Shan Bian, Xiao Mao
2025, 52(10): 1189-1198. doi: 10.1016/j.jgg.2025.04.004
Abstract:
Mediator Complex Subunit 16 (MED16, MIM: 604062) is a member of the Mediator complex, which controls many aspects of transcriptional activity in all eukaryotes. Here, we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing. The affected individuals present with global developmental delay, intellectual disability, and dysmorphisms. To assess the pathogenicity of the variants, functional studies are performed in Drosophila and patient-derived cells. The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system (CNS). Loss of med16 leads to a reduction in eclosion and lifespan, as well as impaired synaptic transmission. In neurons differentiated from the patient-derived induced pluripotent stem cells (iPSCs), the neurite outgrowth is impaired and rescued by expression of exogenous MED16. The patient-associated variants behave as loss-of-function (LoF) alleles in flies and iPSCs. Additionally, the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls. In summary, our findings support that MED16 is important for appropriate development and function, and that biallelic MED16 variants cause a neurodevelopmental disease.
Diverse functions of sex determination gene doublesex on sexually dimorphic neuronal development and behaviors
Jiangtao Chen, Wen Tu, Ziqi Li, Mingze Ma, Simei Jiang, Wenyue Guan, Rong Wang, Yufeng Pan, Qionglin Peng
2025, 52(10): 1199-1210. doi: 10.1016/j.jgg.2025.02.005
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Sex-specific neurons play pivotal roles in regulating sexually dimorphic behaviors. In insects, the sex determination gene doublesex (dsx) establishes major sexual dimorphism of the nervous system, in which male-specific dsxM promotes neuronal development, while female-specific dsxF inhibits neuronal development by promoting neuronal apoptosis. In this study, we find that dsx regulates the number of dsx-expressing central neurons in Drosophila in cell-specific manners. Although dsxM overall promotes an increase in the number of dsx neurons, it inhibits the emergence of specific pC1 neurons. dsxF reduces the number of different pC1/pC2 subtypes, but promotes the formation of pC1d. We also find that dsxM and dsxF barely affect the number of some pC2 neurons. Changes in the number of pC1/pC2 neurons alter their roles in regulating different behaviors, including courtship, aggression, and locomotion. Our results illustrate the multifaceted functions of dsx in sexually dimorphic neuronal development and behaviors.
The phospholipid scramblase PLSCR5 is regulated by POU4F3 and required for hair cell stereocilia homeostasis and auditory functions
Sihao Gong, Qing Liu, Haibo Du, Linqing Zhang, Chengwen Zhu, Zhigang Xu, Xia Gao, Guang-Jie Zhu, Guoqiang Wan
2025, 52(10): 1211-1223. doi: 10.1016/j.jgg.2025.03.003
Abstract:
Hearing relies on the structural and functional integrity of cochlear hair cells, particularly their apical F-actin-filled stereocilia. Phospholipid scramblases are important for maintaining membrane asymmetry, but their roles in the stereocilia and auditory functions are not fully understood. Here, we identify Plscr5 as a downstream target of the transcription factor POU4F3 essential for hair cell function, whose mutation causes human DFNA15 deafness. Plscr5 knockout mice exhibit progressive hearing loss due to stereocilia degeneration and hair cell loss. Functional analyses reveal that PLSCR5 contributes to phosphatidylserine externalization in hair cell apical membranes, particularly in inner hair cells, and is important for outer hair cell and stereocilia maintenance. Our findings highlight PLSCR5 as an important downstream effector of POU4F3 and regulator of phosphatidylserine externalization and membrane dynamics required for auditory functions.
Coordinated regulation of cortical astrocyte maturation by OLIG1 and OLIG2 through BMP7 signaling modulation
Ziwu Wang, Yu Tian, Tongye Fu, Feihong Yang, Jialin Li, Lin Yang, Wen Zhang, Wenhui Zheng, Xin Jiang, Zhejun Xu, Yan You, Xiaosu Li, Guoping Liu, Yunli Xie, Zhengang Yang, Dashi Qi, Zhuangzhi Zhang
2025, 52(10): 1224-1237. doi: 10.1016/j.jgg.2025.03.008
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Astrocyte maturation is crucial for brain function, yet the mechanisms regulating this process remain poorly understood. In this study, we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation. We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression. Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology, including reduced process complexity and an immature gene expression profile. Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state, marked by elevated levels of HOPX and GFAP, resembling human astrocytes. Mechanistically, Olig1 and Olig2 bind directly to the Bmp7 enhancer, repressing its expression to promote astrocyte maturation. Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants, confirming the critical role of BMP7 signaling in this process. These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation, with potential implications for understanding glial dysfunction in neurological diseases.
Varying Bifidobacterium species in the maternal-infant gut microbiota correlate with distinct early neurodevelopmental outcomes
Cong Liu, Qun Lu, Qi Xi, Shuxin Xiao, Jiangbo Du, Rui Qin, Jinghan Wang, Bo Xu, Xiumei Han, Kun Zhou, Shiyao Tao, Hong Lv, Yangqian Jiang, Tao Jiang, Kan Ye, Guangfu Jin, Hongxia Ma, Yankai Xia, Hongbing Shen, Xingyin Liu, Yuan Lin, Zhibin Hu
2025, 52(10): 1238-1245. doi: 10.1016/j.jgg.2025.01.015
Abstract:
The impact of mother-infant microbiota on neurodevelopment is an area of interest, but longitudinal studies are scarce. Using a cohort of 520 families from the Jiangsu birth cohort in China, we reveal that the maternal gut microbiota during early pregnancy play a substantial role, accounting for 3.34% of the variance in offspring neurodevelopmental scores. This contribution is notably higher than the 1.24% attributed to the infants’ own microbiota at 1 year of age, underscoring the significant influence of maternal gut health on early child development. Remarkably, an elevation in maternal Bifidobacterium pseudocatenulatum is linked to decreased cognitive scores, whereas an enrichment of Bifidobacterium longum at 1 year of age is associated with higher cognitive scores. Furthermore, we find that maternal B. pseudocatenulatum is linked to the heterolactic fermentation metabolic pathway, while infant B. longum is associated with the Bifidobacterium shunt pathway. In summary, our analysis implies that maternal and infant gut microbiota play a distinct role in neurodevelopment, suggesting potential strategies for improving neurodevelopmental outcomes during early pregnancy or infant development by targeting gut microbiota composition.
Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder
Congcong Chen, Songwei Guo, Yanan Shi, Xinyu Gu, Ziye Xu, Yingjia Chen, Yayun Gu, Na Qin, Yue Jiang, Juncheng Dai, Yuanlin He, Xiao Han, Yan Liu, Zhibin Hu, Xiaoyan Ke, Cheng Wang
2025, 52(10): 1246-1258. doi: 10.1016/j.jgg.2025.07.008
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder where de novo mutations play a significant role. Although coding mutations in ASD have been extensively characterized, the impact of non-coding de novo mutations (ncDNMs) remains less understood. Here, we integrate cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts. Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects, including 137 down-regulated regulatory mutations (DrMuts) and 101 up-regulated regulatory mutations (UrMuts). Subsequent association analyses reveal that only DrMuts regulating loss-of-function (LoF) intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD (Odds ratio = 4.34; P = 0.001). A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified, including 12 recognized and 29 unreported genes. Interestingly, these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations. Our study introduces an optimized approach for elucidating the functional roles of ncDNMs, thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.
Rapamycin alleviates neurodegeneration in a Drosophila model of spinocerebellar ataxia type 51
Cuijie Wei, Taoyun Ji, Jin Xu, Yilei Zheng, Fuze Zheng, Suxia Wang, Chao Gao, Yalan Wan, Zhenyu Li, Jianwen Deng, Hui Xiong
2025, 52(10): 1259-1267. doi: 10.1016/j.jgg.2025.08.010
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Abstract:
Spinocerebellar ataxia (SCA) type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene. These repeats are translated into a glutamine-rich protein, THAP11-polyQ, which forms protein aggregates and exhibits toxicity in cell models; however, the underlying mechanism remains unclear. In this study, we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses. Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss, locomotor deficiency, and reduced survival. RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway, and electron microscopy of transgenic flies shows an increase in multilamellar bodies, suggesting involvement of autophagy in SCA51. Consequently, we treat the fly model with rapamycin, an mTOR inhibitor known to enhance autophagy. This treatment reduces toxic THAP11-polyQ protein aggregates, significantly alleviates neuronal degeneration, and improves locomotor function, consistent with the rescue effects observed upon overexpression of Atg8a. Overall, these findings suggest that the Drosophila model, which recapitulates the neurodegenerative features of SCA51, can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.
ATPase-deficient CHD7 disease variant disrupts neural development via chromatin dysregulation
Guangfu Wang, Zhuxi Huang, Chenxi He, Ze Wang, Shuhua Dong, Ming Zhu, Fei Lan, Wenhao Zhou, Weijun Feng
2025, 52(10): 1268-1282. doi: 10.1016/j.jgg.2025.08.012
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Chromodomain helicase DNA binding protein 7 (CHD7), an ATP-dependent chromatin remodeler, plays versatile roles in neurodevelopment. However, the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood. Here, we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders. Through in vitro neural induction and differentiation assays combined with mouse brain analyses, we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development. Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes, marked by the open chromatin architecture and active histone modifications. Collectively, our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.
Resource
Spatiotemporal dynamics of neuron differentiation and migration in the developing human spinal cord
Yuan Yu, Mengjie Pan, Quanyou Cai, Ziyu Feng, Baomei Cai, Kaixuan Lin, Shangtao Cao, Mingwei Min, Lihui Lin, Yanlin Ma, Jiekai Chen
2025, 52(10): 1283-1295. doi: 10.1016/j.jgg.2025.08.004
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Precise formation of complex neural circuits in the spinal cord, achieved through the integration of diverse neuronal populations, is essential for central nervous system function. However, the specialization and migration of human spinal cord neurons remain poorly understood. In this study, we perform single-cell transcriptome sequencing of human spinal cord from Carnegie Stages (CS) 16–21 and mouse spinal cord from embryonic day (E) 8.0–11.5, complemented by in situ sequencing of human spinal cord (CS 16–20). Our results reveal the critical role of the precursor state in neuronal differentiation and migration, identifying key transcription factors that regulate these processes across species. Notably, each neuronal lineage expresses unique markers as early as the progenitor stage at the spinal cord midline, and subsequently undergoes a shared transcriptional program during precursor commitment that guides migration. This synchronized migration, validated by spatial transcriptomics, occurs in both dorsal and ventral regions. Our findings offer important insights into the migration patterns and regulatory factors that guide spinal cord neuron subtype specification during embryogenesis.
Research Communications
Deep sequencing reveals SLC35A2 somatic variants in MOGHE: molecular and clinical insights
Huaxia Luo, Xiaoqin Ruan, Xianyu Liu, Qingzhu Liu, Yu Sun, Yao Wang, Jixin Zhang, Lixin Cai, Yuwu Jiang, Ye Wu
2025, 52(10): 1296-1299. doi: 10.1016/j.jgg.2025.04.002
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Recapitulation of key phenotypes and pathological features of primary familial brain calcification (PFBC) in a mouse Slc20a2S602W/S602W model
Junyu Luo, Man Jiang, Jun Liu, Xuan Xu, Jing-Yu Liu
2025, 52(10): 1300-1303. doi: 10.1016/j.jgg.2025.08.005
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