The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

Zuliani, Ilaria; Lanzillotta, Chiara; Tramutola, Antonella; Francioso, Antonio; Pagnotta, Sara; Barone, Eugenio; Perluigi, Marzia; Domenico, Fabio Di

doi:10.1007/s13311-020-00978-4

Cited by 13 publications

(16 citation statements)

References 124 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data suggest that the O-GlcNAcylation profile was completely opposite to that examined in the hippocampus and that a direct competition between O-GlcNAcylation/phosphorylation may only occur at brain level, while peripheral alterations are mainly associated with the increase of protein O-GlcNAcylation. These results follow previous data collected in Down syndrome mice [ 55 ] and are in line with the notion that the aberrant increase of peripheral O-GlcNAcylation levels might be related to insulin resistance and to hyperglycemia-induced glucose toxicity [ 56 ]. Afterwards, we evaluated potential alterations occurring on the O-GlcNAc enzymatic machinery with the aim of assessing whether the reduced levels of O-GlcNAcylated proteins in the hippocampus of HFD mice could be the result of the altered OGT/OGA functionality.…”

Section: Resultssupporting

confidence: 92%

“…Although most of the pathological alterations observed in HFD mice are similar to those of other neurodegeneration models, the mechanisms underlying disturbances of O-GlcNAc homeostasis in the brain of HFD mice have different origins. We previously observed in the hippocampus of a mouse model of DS, the hyperactivation of OGA [ 55 ], but HFD mice did not show any significant increase in the removal of O-GlcNAc moiety. Rather the attention must be focused on the observed alteration of the hippocampal metabolic status associated with the development of insulin resistance.…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

Zuliani

Lanzillotta

Tramutola

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 93%

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

Zuliani

Lanzillotta

Tramutola

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Here also we observed that the reduction of autophagy, demonstrated by altered LC3 II/I, Atg12/5 and Atg7 levels, contributed to the increase of oxidative stress, to defective UPS and to the alteration of early synaptic proteins in Ts65Dn mice [ 63 , 187 ]. Similarly, the alteration of autophagy was also observed in Ts2Cje mice [ 56 ].…”

Section: Stress Responses In Down Syndrome Brainmentioning

confidence: 90%

“…Due to the important role of insulin signaling pathway in the regulation of brain functions, the development of brain insulin resistance seems to be highly implicated in the promotion of AD-like dementia in DS, representing a key pathological event. Moreover, recent evidence from our lab suggest a role for the nutrient-related dynamic changes of O-GlcNAcylation in the progression of DS neuropathology [ 56 ].…”

Section: Brain Pathology In Down Syndromementioning

confidence: 99%

“…In a following study we demonstrated that a decrease of protein-bound HNE levels improved arginase-1 and protein phosphatase 2A activity [ 63 ]. Lately, we demonstrated that rescuing protein O-GlcNAcylation levels in Ts2Cje mice by intranasal Thiamet G administration (25μg/mouse; 2 times/day for 5 days) boosted autophagy induction favoring the restoration of proteostasis [ 56 ]. Alldred and colleagues in 2019 examined the impact of perinatal maternal choline supplementation in Ts65Dn mouse to discern the effects on gene expression within adult offspring at ~6 and 11 months of age [ 224 ].…”

Section: Targeting Stress Responses In Down Syndrome Brainmentioning

confidence: 99%

See 1 more Smart Citation

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Lanzillotta

Domenico

2021

Biomolecules

Self Cite

View full text Add to dashboard Cite

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.

show abstract

Redox imbalance and metabolic defects in the context of Alzheimer disease

Di Domenico,

Lanzillotta,

Perluigi

2024

FEBS Letters

View full text Add to dashboard Cite

Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration.

show abstract

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

Cited by 13 publications

References 124 publications

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Redox imbalance and metabolic defects in the context of Alzheimer disease

Contact Info

Product

Resources

About