Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer's Disease

Supnet, Charlene; Bezprozvanny, Ilya

doi:10.3233/jad-2010-100306

Cited by 137 publications

(100 citation statements)

References 124 publications

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“…These initial results were recapitulated experimentally in various model systems expressing FAD-related mutations in PS and the data suggested that in addition to contributing to altered γ-secretase function, PS mutations had a significant impact on Ca 2+ signalling in AD models. These early observations supported the "Ca 2+ hypothesis of AD" which states that deranged Ca 2+ signaling plays an important role in AD pathogenesis [30][31][32][33]36,37].…”

Section: Presenilins and Intracellular Calcium Signalingsupporting

confidence: 62%

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Supnet

Bezprozvanny

2011

Sci. China Life Sci.

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Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca 2+ ) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca 2+ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca 2+ leak function activity and Ca 2+ overload in the ER. These results provided potential explanation for abnormal Ca 2+ signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca 2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.

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Section: Presenilins and Intracellular Calcium Signalingsupporting

confidence: 62%

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Supnet

Bezprozvanny

2011

Sci. China Life Sci.

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“…In aging neurons, however, calcium fluxes become less controlled, leading to calcium overload (115). This excess calcium is associated with increased ROS/RNS production, mitochondrial dysfunction, and ultimately cell death (178). Many neurodegenerative diseases implicate loss of calcium regulation as a molecular basis of disease.…”

Section: A Cytoplasmic Sources Of Rosmentioning

confidence: 99%

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

Liedhegner

Gao

Mieyal

2012

Antioxidants & Redox Signaling

107

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Significance: Neurodegenerative diseases are characterized by progressive loss of neurons. A common feature is oxidative stress, which arises when reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) exceed amounts required for normal redox signaling. An imbalance in ROS/RNS alters functionality of cysteines and perturbs thiol-disulfide homeostasis. Many cysteine modifications may occur, but reversible protein mixed disulfides with glutathione (GSH) likely represents the common steady-state derivative due to cellular abundance of GSH and ready conversion of cysteine-sulfenic acid and S-nitrosocysteine precursors to S-glutathionylcysteine disulfides. Thus, S-glutathionylation acts in redox signal transduction and serves as a protective mechanism against irreversible cysteine oxidation. Reversal of protein-S-glutathionylation is catalyzed specifically by glutaredoxin which thereby plays a critical role in cellular regulation. This review highlights the role of oxidative modification of proteins, notably S-glutathionylation, and alterations in thiol homeostatic enzyme activities in neurodegenerative diseases, providing insights for therapeutic intervention. Recent Advances: Recent studies show that dysregulation of redox signaling and sulfhydryl homeostasis likely contributes to onset/progression of neurodegeneration. Oxidative stress alters the thiol-disulfide status of key proteins that regulate the balance between cell survival and cell death. Critical Issues: Much of the current information about redox modification of key enzymes and signaling intermediates has been gleaned from studies focused on oxidative stress situations other than the neurodegenerative diseases. Future Directions: The findings in other contexts are expected to apply to understanding neurodegenerative mechanisms. Identification of selectively glutathionylated proteins in a quantitative fashion will provide new insights about neuropathological consequences of this oxidative protein modification. Antioxid. Redox Signal. 16, 543-566.

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“…Neuronal Ca 2+ is normally stored in membrane compartments such as ER, mitochondria, nuclear envelope and neurotransmitter vesicles (Verkhratsky & Petersen, 1998). Compromise of these membranebounded organelles results in a loss of homeostatic intracellular Ca 2+ control, another prominent chemical lesion in AD pathogenesis (LaFerla, 2002;Supnet & Bezprozvanny, 2010). Cytoplasmic Ca 2+ is a pivotal neuronal signal regulating multiple intraneuronal activities, neural functions and synaptic plasticity.…”

Section: Lysosome-derived Chemical Lesions and Subcellular Damagementioning

confidence: 99%