DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons

Klofas, Lindsay K.; Short, Brittany Parker; Snow, John P.; Sinnaeve, Justine; Rushing, Gabrielle V.; Westlake, Grant; Weinstein, Will; Ihrie, Rebecca A.; Ess, Kevin C.; Carson, Robert P.

doi:10.1016/j.nbd.2020.104975

Cited by 15 publications

(16 citation statements)

References 57 publications

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“…Depdc5 , which was also significantly down-regulated in FFI, encodes a subunit of the TORC1 inhibitor complex GATOR1, involved in amino acid–dependent TORC1 activation, and is associated with epilepsy. Haploinsufficiency of Depdc5 in induced pluripotent stem cells causes aberrant morphology and TORC1 hyperactivation ( 37 ), suggesting that down-regulation of Depdc5 in our model may have considerable impact, despite the small fold change. Recent publications revealed that loss of Tsc1–mediated mTOR inhibition results in a shift of electrophysiological properties in a subset of SST + cortical interneurons ( 38 ), suggesting mTOR activity in maintenance of cell identity in SST + neurons.…”

Section: Discussionmentioning

confidence: 99%

Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons

et al. 2022

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Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt–Jakob disease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type–specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unexpectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

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Section: Discussionmentioning

confidence: 99%

Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons

et al. 2022

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“…Neural progenitor cells show increased mTOR activity and increased proliferation rates while simultaneously enlarging soma size. Neurons are also observed to have increased soma size indicative of mTOR hyperactivation [154].…”

Section: Depdc5mentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

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Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

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“…Haploinsu ciency of Depdc5 causes aberrant morphology and TORC1 hyperactivation in induced pluripotent stem cells (43), suggesting that downregulation of Depdc5 in our model may have considerable impact, despite the mild fold change. Histone deacetylase 6, Hdac6, which was down-regulated in FFI and strongly co-expressed with Depdc5, is suggested to be a modulator of TORC1 signaling (44) and central in inducing autophagy as a compensatory mechanism for impaired ubiquitin-proteasome system degradation (45).…”

Section: Mtorc1 Inhibitors Are Downregulated In Sst + Neuronsmentioning

confidence: 92%

Translational profiling of neuronal subtypes in pre-symptomatic fatal familial insomnia mice reveals TOR signaling in somatostatin-expressing neurons

Bauer

Dittrich

Kaczmarczyk

et al. 2022

Preprint

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BackgroundSelective neuronal vulnerability is a common, yet poorly understood characteristic of neurodegenerative diseases. It is particularly fascinating in familial prion diseases, such as fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD), where different mutants of the prion protein manifest as clinically and neuropathologically distinct diseases. MethodsTo determine how distinct neurons respond to different mutations in the prion protein gene at pre-symptomatic stages, we used RiboTag to isolate cell type-specific, translating mRNA from GABAergic, glutamatergic, somatostatin- (SST) and parvalbumin- (PV) expressing neurons of 9-month-old knock-in mouse models of FFI and CJD. Differential gene expression analysis followed by gene set enrichment analysis (GSEA) was performed for all cell types in both diseases. We further constructed a undirected weighted gene co-expression network for SST neurons to identify functional models and hub genes.ResultsWe found SST+ neurons showed the most prominent gene expression changes in both diseases, especially in FFI, with high similarities between the two diseases. GSEA demonstrated similar enrichment patterns of functional terms for GABAergic cell types in both FFI and CJD, whereas responses in glutamatergic neurons were disease specific. For SST+ neurons, functional analysis revealed upregulation of ribosomal biogenesis, mitochondrial function and neurodegenerative disease pathways, and downregulation of synaptic function and small GTPase mediated signaling in FFI. Analysis of an SST co-expression network revealed a disease-associated module, functionally associated with autophagy and TORC1 signaling. Of the identified module hub genes, three were further significantly differentially expressed in FFI SST neurons, including Depdc5, a component of mTOR regulator complex GATOR1, and Nucleosome Remodeling Deacetylase complex component Mta3. Importantly, the molecular changes reported here were very different from those reported for an acquired prion disease model.ConclusionsThis study identifies SST neurons as an early affected cell type, showing similar responses in both FFI and CJD with downregulation of mTOR signaling as a potential explanatory mechanism underlying many of the observed changes. The observation that FFI and CJD have such similar cellular and molecular signatures indicates that a common therapy may be effective for multiple inherited prion diseases, but possibly less effective for acquired prion disease.

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DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons

Cited by 15 publications

References 57 publications

Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons

Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Translational profiling of neuronal subtypes in pre-symptomatic fatal familial insomnia mice reveals TOR signaling in somatostatin-expressing neurons

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