Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Perluigi, Marzia; Pupo, Gilda; Tramutola, Antonella; Cini, Chiara; Coccia, Raffaella; Barone, Eugenio; Head, Elizabeth; Butterfield, D. Allan; Domenico, Fabio Di

doi:10.1016/j.bbadis.2014.04.007

Cited by 137 publications

(139 citation statements)

References 76 publications

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“…Among the putative mechanisms proposed to be common factors in DS and AD neuropathology, defects in PQC have emerged as a unifying mechanism triggering neurodegeneration (4). Previous studies from our group demonstrate impairments of the proteasome system (17) and the reduction of autophagosome function in DS, before and after the development of AD, which suggests that accumulation of oxidized/misfolded protein is an early hallmark in DS brain (59). We showed that some members of the PQC are oxidatively modified in young DS cases before the development of AD and that oxidation of target proteins possibly leads to impaired activity of clearance systems (19).…”

Section: Discussionsupporting

confidence: 55%

“…Accordingly, the Nixon group has demonstrated reduced acidification of lysosomes in AD (73), and genetic mutation of lysosomal ATPase is among the risk factors recognized to contribute to autophagy-related neurodegenerative diseases (37,52). Furthermore, disturbance of autophagosome formation coupled with hyperactivation of the mTOR pathway is observed in DS brain, before and after development of AD pathology (59). Our current observation that V 0 -type ATPase is increasingly polyubiquitinated in DS/ AD brain compared with DS brain suggests that this protein accumulates with aging in DS.…”

Section: Discussionmentioning

confidence: 99%

“…A subset of these autopsy cases was used in previous experiments measuring insoluble Ab, total oxidation, and autophagy pathway as a function of age in DS (9,19,59).…”

Section: Subjectsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…DS patients develop Alzheimer-like dementia by the age of 50; however, the neuropathology of AD, in DS, is complex and likely involves impaired mitochondrial function, defects in neurogenesis, increased OS and altered proteostasis [18]. Recent studies from our laboratory reported, in human DS samples, the early accumulation of protein oxidative damage concomitant with the alteration of mTOR/autophagy signaling; however, the relationship between these events needs to be clarified [19,20,21]. To this purpose, we analyzed the extent of protein oxidation together with the integrity of the mTOR axis in Ts65Dn mice at different ages.…”

Section: Introductionmentioning

confidence: 99%

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

et al. 2015

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Background: Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Down's syndrome (DS) and Alzheimer's disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-β deposition, and aberrant activity of protein degradative systems. Summary: This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. Key Messages: Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies.

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“…Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls cell survival and growth and is often found to be dysregulated in many diseases (6,7,8). mTOR functions by forming two different protein complexes; mTORC1 and mTORC2 (9).…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Hussain

Al-Romaizan

Ahmed

et al. 2015

Mol Med

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Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.

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Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Cited by 137 publications

References 76 publications

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

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

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

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