Alzheimer Presenilins in the Nuclear Membrane, Interphase Kinetochores, and Centrosomes Suggest a Role in Chromosome Segregation

Li, Jinhe; Xu, Min; Zhou, Hui; Ma, Joongsoo; Potter, Huntington

doi:10.1016/s0092-8674(00)80356-6

Cited by 204 publications

(123 citation statements)

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“…7B). These findings are in agreement with the known subcellular location of presenilins in other cells types (35,36). In human islets, reducing the glucose or blocking RyR dramatically increased presenilin-1 levels, whereas blocking IP 3 R or SERCA did not (Fig.…”

Section: Role Of Specific Er Ca 2ϩ Channels In Hypoxia-inducible Factsupporting

confidence: 90%

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: Role Of Specific Er Ca 2ϩ Channels In Hypoxia-inducible Factsupporting

confidence: 90%

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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“…In support of this hypothesis, abnormal segregation of chromosomes has been reported in fibroblast cells bearing certain presenilin-1 mutations (Li et al, 1997;Geller and Potter, 1999). Our results suggest that the extent of chromosomal imbalance in Alzheimer's disease does exist, but it represents f ull DNA replication rather than a specific nondisjunction-induced trisomy of chromosome 21.…”

Section: Discussionsupporting

confidence: 78%

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

2001

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Alzheimer's disease (AD) is a devastating dementia of late life that is correlated with a region-specific neuronal cell loss. Despite progress in uncovering many of the factors that contribute to the etiology of the disease, the cause of the nerve cell death remains unknown. One promising theory is that the neurons degenerate because they reenter a lethal cell cycle. This theory receives support from immunocytochemical evidence for the reexpression of several cell cycle-related proteins. Direct proof for DNA replication, however, has been lacking. We report here the use of fluorescent in situ hybridization to examine the chromosomal complement of interphase neuronal nuclei in the adult human brain. We demonstrate that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in AD have fully or partially replicated four separate genetic loci on three different chromosomes. Cells in unaffected regions of the AD brain or in the hippocampus of nondemented age-matched controls show no such anomalies. We conclude that the AD neurons complete a nearly full S phase, but because mitosis is not initiated, the cells remain tetraploid. Quantitative analysis indicates that the genetic imbalance persists for many months before the cells die, and we propose that this imbalance is the direct cause of the neuronal loss in Alzheimer's disease. Key words: cell cycle; PCNA; cyclin B; hippocampus; nucleus basalis; FISH (fluorescent in situ hybridization); neurodegenerationThe death of nerve cells during early development is a constructive part of pruning and shaping the emerging nervous system. The loss of neurons during adult life, however, is a pathological process that produces behavioral disorders and potentially the death of the organism. Recently, several laboratories have offered evidence that an attempt by the cell to reenter a mitotic cycle precedes many instances of neuronal death (Smith and Lippa, 1995;Arendt et al., 1996Arendt et al., , 1998aVincent et al., 1996Vincent et al., , 1997Vincent et al., , 1998McShea et al., 1997McShea et al., , 1999Nagy et al., 1997aNagy et al., , 1998Busser et al., 1998;Smith et al., 1999). Together, these studies suggest that the paradoxical association of the generative process of cell division with the degenerative process of cell death is found at all stages of the existence of a neuron. The prohibition against cell division begins at the earliest stages of maturation of a neuron. Hindbrain neurons in mice lacking the retinoblastoma tumor suppressor gene are unable to avoid reentering the cell cycle and die by apoptosis immediately after their emigration from the ventricular zone (Lee et al., 1994). Neuronal cell death later in development has also been linked to ectopic cell cycling. Using mutant models of target-related cell death, Herrup and Busser (1995) showed that target-deprived neurons initiated the synthesis of cell cycle enzymes [cyclin D and proliferating cell nuclear antigen (PCNA)] and incorporated bromodeoxyuridine (BrdU) into high molecular weight DN...

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“…Similarly, two polymorphisms in PS-1, one in the coding sequence and one in the promoter have been found to be associated with both an increased risk of AD and an increased incidence of Down syndrome offspring due to chromosome missegregation during meiosis [24,29]. The finding of endogenous presenilin proteins in structures related to mitosis-centrosomes, kinetochores, and the nuclear envelope -also suggests that PS-1 and 2 play a role in the cell cycle and chromosome segregation [13,18,22]. Significantly, the microtubule-associated protein CLIP 170, which is also present in the centrosome and is required for centrosome function, binds to presenilin and is essential for the γ-secretase processing of APP into Aβ [17,40].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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Mutations in the presenilin 1 gene cause most early-onset familial Alzheimer's disease (FAD). Here we report that a defect in the cell cycle-improper chromosome segregation-can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knockin mice are aneuploid by metaphase chromosome analysis and in situ hybridization, 2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 hours, including trisomy 21. 3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.

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Alzheimer Presenilins in the Nuclear Membrane, Interphase Kinetochores, and Centrosomes Suggest a Role in Chromosome Segregation

Cited by 204 publications

References 64 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

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

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