Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca2+ disruptions

Toglia, Patrick; Cheung, King‐Ho; Mak, Don‐On Daniel; Ullah, Ghanim

doi:10.1016/j.ceca.2016.02.013

Cited by 35 publications

(37 citation statements)

References 53 publications

(81 reference statements)

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“…The three mammalian IP 3 R isoforms contain 2700-2800 amino acid residues and share 60-70% sequence [105][106][107][108][109][110][111][112][113][114][115] identity and a common domain structure [22]. Recently the near-atomic (4.7 A) resolution cryo-electron microscopy (cryo-EM) structure of unbound IP 3 R1 purified from rat cerebellum was reported by Serysheva's group [23].…”

Section: Structure Function and Regulation Of Ip 3 Rsmentioning

confidence: 99%

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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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Section: Structure Function and Regulation Of Ip 3 Rsmentioning

confidence: 99%

“…No mPTP opening occurred in control WT cells whereas mPTP opened in cells with mutant PS [113]. It was reasoned that mutant PS causes disturbed IICR that activates the mitochondrial calcium uniporter leading to the mPTP opening and eventually to cell death [113,114].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

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

Egorova

Bezprozvanny

2018

The FEBS Journal

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“…Ca 2+ released from the ER is also buffered by mitochondria that affects the production of ATP and reactive species among other things. Models for mitochondrial function and Ca 2+ buffers are based on our previous work [34, 35] and the functional forms for Ca 2+ leak and SERCA fluxes are adopted from [36]. To complete the computational framework for all the pathways shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

et al. 2018

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Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca rise on the many intracellular Ca-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP) receptor (IPR) and fluorescence imaging of whole-cell Ca response, induced by exogenously applied intracellular Aβ oligomers to show that Aβ inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IPR, which is then extended to build a model for the whole-cell Ca signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca release from the endoplasmic reticulum by intracellular Aβ oligomers through G-protein-mediated stimulation of IP production. The estimated IP concentration as a function of intracellular Aβ content together with the whole-cell model allows us to show that Aβ oligomers impair mitochondrial function through pathological Ca uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and HO. We further show that mitochondrial function can be restored by the addition of Ca buffer EGTA, in accordance with the observed abrogation of Aβ cytotoxicity by EGTA in our live cells experiments.

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“…Mitochondrial function influences AD, APP expression and processing and Aß accumulation [101,102]. Also in familiar AD (FAD), the impaired mitochondrial function is caused by PS (either PS 1 or PS 2) mutations, but about 10% are inherited, most of the cases are sporadic AD (SAD).…”

Section: Mitochondria Aging and Admentioning

confidence: 99%

Alzheimer's Disease: From Animal Models to the Human Syndrome

Orta‐Salazar¹,

Vargas‐Rodríguez²,

Castro-Chavira³

et al. 2016

Update on Dementia

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Some animal models, genetically modified (such as murine) and sporadic (as others species), enable the study of the origin of specific lesions observed in human neurodegenerative diseases. In particular, Alzheimer's disease (AD) models have been designed to test the hypothesis that certain lesions are associated with functional and morphological changes beginning with memory loss and impairment in activities of daily life. This review compares and evaluates the phenotypes of different AD animal models, on the basis of the specific objectives of each study, with the purpose of encompassing their contributions to the comprehension of the AD signs and symptoms in humans. All these models contribute to the comprehension of the human AD mechanisms regarding the heterogeneity of AD phenotypes: the overlap between AD and age-related changes, the variability of AD onset (early or late), the probable reactiveness of amyloid-β and tau proteins, the scarcity of senile plaques and/or neurofibrillary tangles in some AD cases, the spatial correlation of the pathology and cerebral blood vessels, and the immunological responses (microglial aging) and synaptopathy. Altogether, these considerations may contribute to find therapies to treat and prevent this disease.

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Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca2+ disruptions

Cited by 35 publications

References 53 publications

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

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

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

Alzheimer's Disease: From Animal Models to the Human Syndrome

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