β-Amyloid Mediated Nitration of Manganese Superoxide Dismutase

Muthuswamy, Anantharaman; Tangpong, Jitbanjong; Keller, Jeffrey N.; Murphy, Michael P.; Markesbery, William R.; Kiningham, Kelley K.; Clair, Daret K. St.

doi:10.2353/ajpath.2006.051223

Cited by 129 publications

(44 citation statements)

References 74 publications

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“…In the ␤-cell, presenilins appear to participate in a signaling network implicated in mitochondrial function and cell fate. Interestingly, presenilin-1 has been localized to the mitochondria in other cell types (62,63) and mitochondrial respiration was decreased in knock-in mice with a presenilin-1 gain-of-function mutation (64). Studies also point to the up-regulation of presenilins in hypoxic conditions (12,24,27,65), similar to our observation that hypoglycemia increases presenilin-1 expression.…”

Section: Discussionsupporting

confidence: 75%

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Dror¹,

Kalynyak

Bychkivska

et al. 2008

Journal of Biological Chemistry

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Pancreatic ␤-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca 2؉ stores activates calpain-10-dependent apoptosis in ␤-cells. In the present study, we further characterized intracellular Ca 2؉ channel expression and function in human islets and the MIN6 ␤-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca 2؉ flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1␤). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1␤ and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1␤, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in ␤-cells. We demonstrate that this pathway is controlled by Ca 2؉ flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca 2؉ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.

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Section: Discussionsupporting

confidence: 75%

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Dror¹,

Kalynyak

Bychkivska

et al. 2008

Journal of Biological Chemistry

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“…Such data suggest that non-genetic manipulations that alter MnSOD levels can affect both cognitive and amyloidogenic aspects of AD. In support of MnSOD alterations as occurring secondary to other disturbances, APP/PS1 had no decrease in MnSOD protein levels at varying ages (2–14 mos) in either WT (APP/PS1 heterozygotes) or Tg (APP/PS1 homozygotes) lines, whereas MnSOD activity was decreased (Anantharaman et al, 2006). Nitrotyrosine was increased in Tg mice as compared to WT controls and contributed to the decreased enzymatic activation.…”

Section: Manganese Superoxide Dismutase (Mnsod)mentioning

confidence: 97%

“…Nitrotyrosine was increased in Tg mice as compared to WT controls and contributed to the decreased enzymatic activation. These authors suggest Aβ-induced elevations in nitration negatively affect MnSOD activity (Anantharaman et al, 2006). …”

Section: Manganese Superoxide Dismutase (Mnsod)mentioning

confidence: 99%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

132

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Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

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“…A bi-product of this reaction is acrolein which lowers activity of key components of the TCA cycle and binds with mtDNA preventing interactions and altering activity. Additionally Aβ has been implicated in impairing the function of SOD2 in the matrix of mitochondria, thus diminishing the internal defense against superoxide oxidation and leading to a further increase in ROS formation [46]. The increase in ROS and decrease in metabolic rate that occurs as a result of an import of Aβ in mitochondria gradually leads to reduced energy production and eventual cell death.…”

Section: Alzheimer Diseasementioning

confidence: 99%

Mitochondrial dynamics in degenerative disease and disease models

Merzetti¹,

Staveley

2013

Neurosci Discov

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Degenerative diseases cause the breakdown or destruction of a cell or group of cells over a period of time, leading to an array of physical or cognitive symptoms including impaired motor skills, memory loss and dementia. Often, degenerative diseases have been characterized as afflictions of the elderly but earlier onset forms of these diseases have been linked to genetic dysfunction. Mutant forms of genes often lead to the breakdown of the cell via interference with internal pathways involved in the removal of impaired cellular components and energy production. Mitochondria are dynamic organelles involved in cellular energy production and in intra-cellular signalling leading to cell death. The proper function and upkeep of these organelles is essential to maintaining a healthy cellular environment and preventing accumulation of harmful oxidative free radicals. Breakdown and improper functioning of mitochondria has been linked to the onset of a number of diverse neurological diseases including Alzheimer Disease, Huntington Disease, Parkinson Disease, Multiple Sclerosis, retinal abnormalities and muscle neuron linked motor impairment. In this review, we examine the role of mitochondria in degenerative disease and highlight common mechanisms of disease progression as well as potential targets for future therapeutic approaches.

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β-Amyloid Mediated Nitration of Manganese Superoxide Dismutase

Cited by 129 publications

References 74 publications

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Mitochondrial dynamics in degenerative disease and disease models

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