Chronic Suppression of Inositol 1,4,5-Triphosphate Receptor-Mediated Calcium Signaling in Cerebellar Purkinje Cells Alleviates Pathological Phenotype in Spinocerebellar Ataxia 2 Mice

Kasumu, Adebimpe W.; Liang, Xia; Egorova, Polina A.; Vorontsova, Daria; Bezprozvanny, Ilya

doi:10.1523/jneurosci.1643-12.2012

Cited by 105 publications

(147 citation statements)

References 46 publications

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“…In both SCA2 and SCA3, the polyQ-expanded form of the protein binds to the IP 3 receptor and increases IP 3 -mediated calcium release [106,107]. Furthermore, chronic suppression of IP 3 signaling in vivo reduces neuronal dysfunction and cell death in a transgenic mouse model of SCA2 [108] and SCA3 [106]. Taken together, these data support a role for increased IP 3 -mediated calcium release in the pathogenesis of SCA2 and SCA3.…”

Section: Pathologic Calcium Handling In Polyq Disordersmentioning

confidence: 65%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

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Section: Pathologic Calcium Handling In Polyq Disordersmentioning

confidence: 65%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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“…In this regard, our proteomic screen also revealed that a significant number of mitochondrial proteins involved in the ETC complexes and the ATP synthase were downregulated in mutant PCs, thereby affecting bioenergetics and proper mitochondrial functioning. Additionally, it is well accepted that calcium signaling is impaired in SCA1, SCA2 and SCA3 (Brown and Loew, 2012;Halbach et al, 2016;Kasumu et al, 2012;Pellistri et al, 2013) and as mitochondria are the second most important calcium storage organelle, improper mitochondrial functioning can negatively impact calcium homeostasis and neuronal transmission (Wang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Stucki

Ruegsegger

Steiner

et al. 2016

Free Radical Biology and Medicine

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Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…4) [90]. Patchclamp experiments on cerebellar slices showed that virus-mediated IP 3 phosphatase overexpression improved age-dependent impairment in the electrophysiological activity of SCA2 PCs.…”

Section: Spinocerebellar Ataxia Types 2 Andmentioning

confidence: 99%

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

Egorova

Bezprozvanny

2018

The FEBS Journal

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The inositol 1,4,5-trisphosphate receptor (IP 3 R) is an intracellular ion channel that mediates the release of calcium ions from the endoplasmic reticulum. It plays a role in basic biological functions, such as cell division, differentiation, fertilization and cell death, and is involved in developmental processes including learning, memory and behavior. Deregulation of neuronal calcium signaling results in disturbance of cell homeostasis, synaptic loss and dysfunction, eventually leading to cell death. Three IP 3 R subtypes have been identified in mammalian cells and the predominant isoform in neurons is IP 3 R type 1. Dysfunction of IP 3 R type 1 may play a role in the pathogenesis of certain neurodegenerative diseases as enhanced activity of the IP 3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease. These results suggest that IP 3 R-mediated signaling is a potential target for treatment of these disorders. In this review we discuss the structure, functions and regulation of the IP 3 R in healthy neurons and in conditions of neurodegeneration. IntroductionInositol 1,4,5-trisphosphate receptors (IP 3 Rs) are a family of intracellular ion channels that mediate calcium (Ca 2+ ) release from the endoplasmic reticulum (ER) following stimulation by the second messenger inositol 1,4,5-trisphosphate (IP 3 ). Generation of IP 3 molecules is caused by the activation of phospholipase C in response to the activation of G proteincoupled receptors such as serotonergic receptors, adrenergic receptors, calcitonin receptors, histamine receptors, metabotropic glutamate receptors (mGluRs), Abbreviations AAV, adeno-associated virus; AD, Alzheimer's disease; ALG-2, apoptosis-linked gene 2; ARM, armadillo; Ab, beta amyloid; BH, Bcl-2 homology; CaBP1, calcium-binding protein 1; CTD, C-terminal domain; EM, electron microscopy; ER, endoplasmic reticulum; FAD, familial Alzheimer's disease; GRP78, 78-kDa glucose regulated protein; HAP1, huntingtin-associated protein 1; HD, Huntington's disease; HelD, helical domain; Htt, huntingtin; IBC, IP 3 -binding core; IICR, inositol 1,4,5-trisphosphate-induced calcium release; ILD, 'intervening lateral' domain; IP 3 , inositol 1,4,5-trisphosphate; IP 3 R1, IP 3 R type 1; IP 3 R, inositol 1,4,5-trisphosphate receptor; IRBIT, IP 3 R binding protein released with IP 3 ; KO, knock-out; LBD, ligand-binding domain; LNK, helical linker domain; MCI, mild cognitive impairment; mGluR, metabotropic glutamate receptor; mPTP, mitochondrial permeability transition pore; MSN, medium spiny neuron; NMDA, N-methyl-D-aspartate; NTR, Nterminal region; Opt, opisthotonos; PC, Purkinje cell; polyQ, polyglutamine; PS, presenilin; RyR, ryanodine receptor; SAD, sporadic Alzheimer's disease; SCA, spinocerebellar ataxia; SD, IP 3 -binding suppressor domain; SUMF1, sulfatase modifying factor 1; TG2, transglutaminase type 2; TMD, transmembrane domain; WT, wild-type; YAC, yeast artificial chromosome; b-TF, b-trefoil. 3547The (Fig. 1). Upon extracellular stimulation -by various ...

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Chronic Suppression of Inositol 1,4,5-Triphosphate Receptor-Mediated Calcium Signaling in Cerebellar Purkinje Cells Alleviates Pathological Phenotype in Spinocerebellar Ataxia 2 Mice

Cited by 105 publications

References 46 publications

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

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