Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Scheper, Wiep; Hol, Elly M.

doi:10.2174/1568007054038166

Cited by 13 publications

(7 citation statements)

References 98 publications

(154 reference statements)

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“…The system has a crucial role in regulating the cell cycle (Hershko 2005) and transcription (Muratani and Tansey 2003;Auld and Silver 2006), has a main function in synaptic plasticity by regulating the protein composition of the synapse, during modification of the synapse (Yi and Ehlers 2005) and has an essential function in cellular protein quality control (Kopito 2000;De Vrij et al 2004;Scheper and Hol 2005).…”

Section: The Ubiquitin Proteasome System (Ups)mentioning

confidence: 99%

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Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Hol

Scheper

2007

J Mol Neurosci

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Huntington's disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG triplet repeat expansion in the gene encoding the protein huntingtin. The most studied model of HD, the R6/2 transgenic mouse, replicates many features of the disease. In addition to motor, cognitive, and endocrine dysfunctions, these mice exhibit a progressive disruption of circadian rhythms. This is accompanied by an altered expression of the circadian clock genes in the suprachiasmatic nucleus/nuclei (SCN), the principal circadian pacemaker in the brain. The neuropeptide vasoactive intestinal polypeptide (VIP) and its receptor VPAC2 are highly expressed in the SCN, and VIPergic signaling plays an essential role in maintenance of ongoing circadian rhythmicity. We found a marked reduction in both VIP mRNA and VPAC2 receptor mRNA, quantified by RT-PCR, as well as a decrease in VIP immunostaining in the SCN of R6/2 mice. These changes were coupled to a disruption of circadian rhythm. We observed no loss of neurons in the SCN and therefore suggest that the changes in VIP and VPAC2 receptor are due to their decreased expression. In conclusion, we propose that impaired VIPergic signaling is an additional candidate mechanism for disruption of circadian rhythms in R6/2 mice.

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Section: The Ubiquitin Proteasome System (Ups)mentioning

confidence: 99%

“…A retrograde trafficking route from the Golgi to the ER mediated by the small GTPase Rab6 (White et al 1999;Girod et al 1999) may be involved in such a post-ER protein quality control mechanism (Scheper and Hol 2005).…”

Section: Protein Quality Control In the Secretory Pathwaymentioning

confidence: 99%

Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Hol

Scheper

2007

J Mol Neurosci

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“…However, there is accumulating evidence from post-mortem AD and transgenic mouse brains demonstrating the presence of A within neurons (as reviewed in [9]). A is produced intracellularly in a variety of subcellular compartments, including the endoplasmic reticulum (ER), trans-Golgi network and the endo-lysosomal system [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity

Chafekar

Zwart²,

Veerhuis³

et al. 2008

CAR

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Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42. In addition, we showed that oligomeric Abeta1-42 is internalized by cells, whereas fibrillar Abeta1-42 remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta1-42 oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Abeta1-40 and Abeta1-42 compared to the parental line. In addition, APPmut produces more Abeta1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta1-42. Our data indicate that increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

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“…Failure of UPP function has been linked to beta-amyloid (Ab) toxicity in the central nervous system (CNS). 4 UPP dysfunction is also caused by the Ub mutant, UbB þ 1, which accumulates in AD and other tauopathies. [5][6][7] UbB þ 1 is generated by a non-DNA-encoded dinucleotide deletion in the first coding unit of human polyubiquitin B (UbB) transcripts.…”

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Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration

et al. 2007

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A dinucleotide deletion in human ubiquitin (Ub) B messenger RNA leads to formation of polyubiquitin (UbB) þ 1, which has been implicated in neuronal cell death in Alzheimer's and other neurodegenerative diseases. Previous studies demonstrate that UbB þ 1 protein causes proteasome dysfunction. However, the molecular mechanism of UbB þ 1-mediated neuronal degeneration remains unknown. We now report that UbB þ 1 causes neuritic beading, impairment of mitochondrial movements, mitochondrial stress and neuronal degeneration in primary neurons. Transfection of UbB þ 1 induced a buildup of mitochondria in neurites and dysregulation of mitochondrial motor proteins, in particular, through detachment of P74, the dynein intermediate chain, from mitochondria and decreased mitochondria-microtubule interactions. Altered distribution of mitochondria was associated with activation of both the mitochondrial stress and p53 cell death pathways. These results support the hypothesis that neuritic clogging of mitochondria by UbB þ 1 triggers a cascade of events characterized by local activation of mitochondrial stress followed by global cell death. Furthermore, UbB þ 1 small interfering RNA efficiently blocked expression of UbB þ 1 protein, attenuated neuritic beading and preserved cellular morphology, suggesting a potential neuroprotective strategy for certain neurodegenerative disorders.

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Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Cited by 13 publications

References 98 publications

Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration

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Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Cited by 13 publications

References 98 publications

Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Protein Quality Control in Neurodegeneration: Walking the Tight Rope Between Health and Disease

Increased A&#946;1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration

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Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity