Research progress on vesicle cycle and neurological disorders

Zhang, Chengcheng; Zhu, Li‐Juan; Chen, Ce

doi:10.18433/jpps31458

Cited by 10 publications

(2 citation statements)

References 102 publications

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“…This regulatory mechanism depends on a direct interaction of C1ql2 with Nrxn3(25b+). Importantly, SV trafficking and altered release probability have been implicated in neurological and neuropsychiatric disorders (Egbujo et al, 2016 ;Lepeta et al, 2016 ;Zhu et al, 2021 ). Thus, the identification of the Bcl11b/C1ql2/Nrxn3(25b+)-dependent signaling module in this study provides a new entry point for future mechanistic analyses of synaptopathies.…”

Section: Discussionmentioning

confidence: 82%

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Koumoundourou,

Rannap,

De Bruyckere

et al. 2024

eLife

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The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype, and interferes with C1ql2 targeting to the synapse. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

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Section: Discussionmentioning

confidence: 82%

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Koumoundourou,

Rannap,

De Bruyckere

et al. 2024

eLife

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“…Interestingly, C1ql2 regulates synaptic vesicle recruitment to the active zone through direct interaction with Nrxn3(25b+), a specific splice variant of neurexin-3 that was linked to NDDs before [89,90]. Changes in synaptic signal transduction, including establishment, transport, and release of synaptic vesicles, as well as alterations on the postsynaptic side are known to be hallmarks of NDDs [91][92][93]. Besides its role in development and maintenance of neocortex and hippocampus, Bcl11b is present in postmitotic but immature neurons of the vomeronasal sensory system.…”

Section: Functions Of Bcl11b In Cns Developmentmentioning

confidence: 99%

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

Seigfried,

Britsch

2024

Biology

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Neurodevelopmental disorders (NDDs) comprise a diverse group of diseases, including developmental delay, autism spectrum disorder (ASD), intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD). NDDs are caused by aberrant brain development due to genetic and environmental factors. To establish specific and curative therapeutic approaches, it is indispensable to gain precise mechanistic insight into the cellular and molecular pathogenesis of NDDs. Mutations of BCL11A and BCL11B, two closely related, ultra-conserved zinc-finger transcription factors, were recently reported to be associated with NDDs, including developmental delay, ASD, and ID, as well as morphogenic defects such as cerebellar hypoplasia. In mice, Bcl11 transcription factors are well known to orchestrate various cellular processes during brain development, for example, neural progenitor cell proliferation, neuronal migration, and the differentiation as well as integration of neurons into functional circuits. Developmental defects observed in both, mice and humans display striking similarities, suggesting Bcl11 knockout mice provide excellent models for analyzing human disease. This review offers a comprehensive overview of the cellular and molecular functions of Bcl11a and b and links experimental research to the corresponding NDDs observed in humans. Moreover, it outlines trajectories for future translational research that may help to better understand the molecular basis of Bcl11-dependent NDDs as well as to conceive disease-specific therapeutic approaches.

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Real‐Time Observation for Dynamic Oscillation during Self‐Assembly and Clearance of Aβ42

Yao

Cheng

et al. 2023

Chemistry A European J

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The dynamic oscillation implicated in structural heterogeneity during the self‐assembly of amyloid peptide 1–42 (Aβ42) may play a crucial role in eliciting cellular responses. We developed a real‐time monitoring platform to observe an oscillatory non‐equilibrium interaction that dominated the Aβ42 clearance by neuronal cells during interplay with an oscillator (lipopolysaccharide, LPS). Molecular dynamics studies indicated that the electrostatic and hydrophobic segments of LPS involved in the temporary heteromolecular association and slightly decelerated the intrinsic thermally–induced protein dynamics of Aβ42. A bait‐specific intervention strategy could temporarily slow down the self‐propagation of Aβ42 to extend the lifetime of autonomous oscillation and augment Aβ42 clearance of neuronal cells. The lifetime increment of oscillation shows a bait concentration‐dependent manner to reflect the non‐equilibrium binding strength. This relationship may serve as a predictor for Alzheimer's disease drug discovery.

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Research progress on vesicle cycle and neurological disorders

Cited by 10 publications

References 102 publications

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

Real‐Time Observation for Dynamic Oscillation during Self‐Assembly and Clearance of Aβ42

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