Regulation of neuronal physiology by Ca2+ release through the IP3R

Hasan, Gaiti; Sharma, Anamika

doi:10.1016/j.cophys.2020.06.001

Cited by 16 publications

(12 citation statements)

References 34 publications

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“…In support of this, we found significant overlap between HDAC4 targets and AT downregulated genes (p-value 6.08e-22, Fisher’s exact test, Figure S5C). Taken together, these findings support that abnormal calcium ion homeostasis may be a direct consequence of ATM loss of function in Purkinje neurons, which may lead to aberrant firing patterns and ataxic phenotypes 31,32 .…”

Section: Resultssupporting

confidence: 62%

ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

Lai

Kim

Jeffries

et al. 2021

Preprint

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While ATM loss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (AT), how this genetic mutation leads to selective and progressive cerebellar degeneration of Purkinje and granule cells remains unknown. We performed single-nucleus RNA-sequencing of the human cerebellum and prefrontal cortex from individuals with AT and matched unaffected controls to identify AT-associated transcriptomic changes in a cell-type- and brain-region-specific manner. We provide the largest single-nucleus transcriptomic atlas of the adult human cerebellum to-date (126,356 nuclei), identify upregulation of apoptotic and ER stress pathways in Purkinje and granule neurons, and uncover strong downregulation of calcium ion homeostasis genes in Purkinje neurons. Our analysis reveals prominent inflammation of microglia in AT cerebellum with transcriptional signatures similar to aging and neurodegenerative microglia, and suggests that microglia activation precedes Purkinje and granule neuron death in disease progression. Our data implicates a novel role of microglial activation underlying cerebellar degeneration in AT.

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Section: Resultssupporting

confidence: 62%

ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

Lai

Kim

Jeffries

et al. 2021

Preprint

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“…Of these, IP 3 R1 is the most prevalent isoform in neurons and is relevant in the context of several neurodegenerative disorders ( Terry et al, 2018 ). Human mutations in IP 3 R1 cause Spinocerebellar ataxia 15 (SCA15), SCA29 and Gillespie syndrome ( Hasan and Sharma, 2020 ). Disease causing IP 3 R1 mutations span different domains but several are clustered in the amino terminal IP 3 binding region, from where they impact ER-Ca 2+ release when tested in mammalian cell lines ( Ando et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

Sharma

Hasan

2020

eLife

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Innate behaviours, although robust and hard wired, rely on modulation of neuronal circuits, for eliciting an appropriate response according to internal states and external cues. Drosophila flight is one such innate behaviour that is modulated by intracellular calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs). Cellular mechanism(s) by which IP3Rs modulate neuronal function for specific behaviours remain speculative, in vertebrates and invertebrates. To address this, we generated an inducible dominant negative form of the IP3R (IP3RDN). Flies with neuronal expression of IP3RDN exhibit flight deficits. Expression of IP3RDN helped identify key flight-modulating dopaminergic neurons with axonal projections in the mushroom body. Flies with attenuated IP3Rs in these presynaptic dopaminergic neurons exhibit shortened flight bouts and a disinterest in seeking food, accompanied by reduced excitability and dopamine release upon cholinergic stimulation. Our findings suggest that the same neural circuit modulates the drive for food search and for undertaking longer flight bouts.

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“…Several other studies suggest a link between intracellular Ca 2+ signaling and histone modifications that regulate transcription (Sharma et al, 2014;Whitlock et al, 1983). Dysfunction of the IP 3 R has been implicated in neurodegenerative conditions such as Alzheimer's, Huntington's disease and spinocerebellar ataxias (Egorova and Bezprozvanny, 2018;Hasan and Sharma, 2020). Rodent models for Alzheimer's disease and accelerated senescence also show a decrease in brain-wide levels of H3K36 methylation (Wang et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

IP3-mediated Ca2+ signals regulate larval to pupal transition under nutrient stress through the H3K36 methyltransferase Set2

et al. 2021

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Persistent loss of dietary protein usually signals a shutdown of key metabolic pathways. In Drosophila larvae that have reached a ‘critical weight’ and can pupariate to form viable adults, such a metabolic shutdown would needlessly lead to death. Inositol 1,4,5-trisphosphate-mediated calcium (IP3/Ca2+) release in some interneurons (vGlutVGN6341) allows Drosophila larvae to pupariate on a protein-deficient diet by partially circumventing this shutdown through upregulation of neuropeptide signaling and the expression of ecdysone synthesis genes. Here, we show that IP3/Ca2+ signals in vGlutVGN6341 neurons drive expression of Set2, a gene encoding Drosophila Histone 3 Lysine 36 methyltransferase. Furthermore, Set2 expression is required for larvae to pupariate in the absence of dietary protein. IP3/Ca2+ signal-driven Set2 expression upregulates key Ca2+-signaling genes through a novel positive-feedback loop. Transcriptomic studies, coupled with analysis of existing ChIP-seq datasets, identified genes from larval and pupal stages that normally exhibit robust H3K36 trimethyl marks on their gene bodies and concomitantly undergo stronger downregulation by knockdown of either the intracellular Ca2+ release channel IP3R or Set2. IP3/Ca2+ signals thus regulate gene expression through Set2-mediated H3K36 marks on select neuronal genes for the larval to pupal transition.

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Regulation of neuronal physiology by Ca2+ release through the IP3R

Cited by 16 publications

References 34 publications

ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

IP3-mediated Ca2+ signals regulate larval to pupal transition under nutrient stress through the H3K36 methyltransferase Set2

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