Defective ubiquitination of cerebral proteins in Alzheimer's disease

Salon, M Lopez; Morelli, Laura; Castaño, Eduardo M.; Soto, Eduardo F.; Pasquini, Juana M.

doi:10.1002/1097-4547(20001015)62:2<302::aid-jnr15>3.0.co;2-l

Cited by 208 publications

(99 citation statements)

References 46 publications

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“…Both of these diseases have been linked to proteasomal and CCT deregulation [38,41]. We suggest a possible mechanism for the inverse association with nicotine is through its effects on the ubiquitin-proteasomal and CCT pathways (Fig.…”

Section: Discussionmentioning

confidence: 85%

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Kane

Konu

Jennie

et al. 2004

Molecular Brain Research

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Previously, we used cDNA microarrays to demonstrate that the phosphatidylinositol and MAP kinase signaling pathways are regulated by nicotine in different rat brain regions. In the present report, we show that, after exposure to nicotine for 14 days, ubiquitin, ubiquitinconjugating enzymes, 20S and 19S proteasomal subunits, and chaperonin-containing TCP-1 protein (CCT) complex members are upregulated in rat prefrontal cortex (PFC) while being downregulated in the medial basal hypothalamus (MBH). In particular, relative to saline controls, ubiquitins B and C were upregulated by 33% and 47% ( Pb0.01), respectively, in the PFC. The proteasome beta subunit 1 (PSMB1) and 26S ATPase 3 (PSMC3) genes were upregulated in the PFC by 95% and 119% ( Pb0.001), respectively. In addition to the protein degradation pathway of the ubiquitin-proteasome complexes, we observed in the PFC an increase in the expression of small, ubiquitin-related modifiers (SUMO) 1 and 2 by 80% and 33%, respectively ( Pb0.001), and in 3 of 6 CCT subunits by up to 150% ( Pb0.0001). To a lesser extent, a change in the opposite direction was obtained in the expression of the same gene families in the MBH. Quantitative real-time RT-PCR was used to validate the microarray results obtained with some representative genes involved in these pathways. Taken together, our results suggest that, in response to systemic nicotine administration, the ubiquitin-proteasome, SUMO, and chaperonin complexes provide an intricate control mechanism to maintain cellular homeostasis, possibly by regulating the composition and signaling of target neurons in a region-specific manner. D

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Section: Discussionmentioning

confidence: 85%

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Kane

Konu

Jennie

et al. 2004

Molecular Brain Research

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“…Evidence is compelling that a decrease in proteasome activity occurs in AD brains (31,32). It is unclear, however, whether this decrease in proteasome activity is in parallel with an increase in A␤ levels.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides

Marambaud

Zhao

Davies

2005

Journal of Biological Chemistry

684

463

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Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4,5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-␤ (A␤) peptides produced from different cell lines. Resveratrol does not inhibit A␤ production, because it has no effect on the A␤-producing enzymes ␤-and ␥-secretases, but promotes instead intracellular degradation of A␤ via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of A␤ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit ␤5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease. Alzheimer's disease (AD)2 is a progressive neurodegenerative disorder leading to the most common form of dementia. Compelling evidence supports the central role of A␤ in the pathogenesis of the disease (1). A␤ is a core component of the senile plaque, a classical lesion found in the neocortex and hippocampus of AD brains, and excessive production of the highly insoluble 42-amino acid-long A␤42 peptide is almost invariably observed in the presence of mutations in the three genes linked to early onset autosomal dominant familial forms of AD (2).In the amyloidogenic pathway, the amyloid-␤ precursor protein (APP) is cleaved by the aspartic protease ␤-secretase/BACE1 to yield the membrane-anchored C-terminal fragments C99 and C89. C99 is then endoproteolyzed by the ␥-secretase proteolytic complex to produce various A␤ peptides. The major cleavage takes place after Val-40 producing A␤40. In an alternative nonamyloidogenic pathway, APP is endoproteolyzed within the A␤ region by ␣-secretase to generate the C-terminal fragment C83 and the soluble N-terminal fragment secreted APP␣. Finally, a ␥-secretase-mediated ⑀-cleavage of APP allows the intracellular release of the transcriptionally active APP intracellular domain (AID (3) or AICD) (4 -6).Epidemiological studies have shown that moderate wine intake reduces the risk of developing AD (7-10). Resveratrol, a polyphenol that occurs in abundance in grapes and red wine, is suspected to afford antioxidant and neuroprotective properties and therefore to contribute to the beneficial effect of wine consumption on the neurodegenerative process (11-13). Here we report that resveratrol has a potent anti-amyloidogenic activity by reducing the levels of A␤ produced from different cell lines expressing wild type or Swedish mutant APP 695 . We show that resveratrol acts by promoting ...

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“…Recent studies from our group and others demonstrated that disturbance of proteolytic machinery is a key feature of degenerating neurons and appears in several neurodegenerative disorders (4,8,15). Proteasome activity was found to be reduced in AD brains than in age-matched controls (38,50) and also in DS brain (17). In addition, high levels of Ub were detected in brain and cerebrospinal fluid samples from AD patients (43).…”

Section: Innovationmentioning

confidence: 99%

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

Tramutola

Domenico

Barone

et al. 2017

Antioxidants & Redox Signaling

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Aims: Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. Results: Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. Innovation: This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. Conclusions: Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26,[280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295][296][297][298]

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Defective ubiquitination of cerebral proteins in Alzheimer's disease

Cited by 208 publications

References 46 publications

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

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