Daughterless, the<i>Drosophila</i>orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

Tamberg, Laura; Jaago, Mariliis; Säälik, Kristi; Shubina, Anastassia; Kiir, Carl Sander; Sirp, Alex; Timmusk, Tõnis; Palgi, Mari

doi:10.1101/792796

Cited by 4 publications

(4 citation statements)

References 70 publications

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“…Interestingly, a study with Drosophila demonstrated that silencing of TCF4 orthologue Da resulted in synaptic and locomotor impairments (Tamberg et al, 2020). These results highlight the important conservation of TCF4 function in several species, especially regarding neurodevelopment.…”

Section: Ndd‐associated Multifactorial Disordersmentioning

confidence: 99%

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Santos-Terra

Deckmann

Fontes-Dutra

et al. 2021

Intl J of Devlp Neuroscience

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Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)—a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis—represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood‐brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location‐dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome‐environment interactions.

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Section: Ndd‐associated Multifactorial Disordersmentioning

confidence: 99%

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Santos-Terra

Deckmann

Fontes-Dutra

et al. 2021

Intl J of Devlp Neuroscience

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“…For the ectopic overexpression in Drosophila , the two-component Gal4-upstream activating sequence (UAS) system is widely exploited (43). We chose the 30Y-Gal4 driver line with specific expression in the Drosophila mushroom body previously shown to be capable to affect also the negative geotaxis (44). For the overexpression we used UAS-APP.Aβ42.D694N.VTR responder line expressing human Aβ with an Iowa mutation from familial AD patients, D23N.…”

Section: Resultsmentioning

confidence: 99%

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

Metsla

Kirss

Laks

et al. 2021

Preprint

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Alzheimer′s disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-beta (Aβ) peptides. Multiple amyloid-targeting drug candidates have recently failed in clinical trials, which creates the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess extracellular copper levels. In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and searched for new copper-regulating ligands. We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in a SH-SY5Y-based neuronal cell model, and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster model of AD from developing AD phenotype, reflecting in decreased locomotor activity. Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD and supports the hypothesis that LA supplementation may serve as a promising cost-effective method for the prevention and/or treatment of AD.

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“…First, we showed that PTHS patient-derived neurons have a reduction in excitatory synapse density (Figure 2G-J; Figure 4E, F), a phenotype that was previously reported in the cortex and hippocampus of two different PTHS mouse models 13 ,54 . Similarly, disruption of Da, the TCF4 orthologue in drosophila, led to decreased levels of the synaptic proteins synapsin and disc large 1 55 . Secondly, we observed a significant reduction in the frequency and amplitude of sEPSCs, which was consistent with synaptic density measurements (Figure 2A-C; Figure 5G-I).…”

Section: Tcf4 Regulates Synaptic Development and Functionmentioning

confidence: 98%

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

Davis

Chen

Ostlund

et al. 2023

Preprint

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Genetic variation in the transcription factor 4 (TCF4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients with TCF4 mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

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Daughterless, theDrosophilaorthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

Cited by 4 publications

References 70 publications

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

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