Emerging roles of N-linked glycosylation in brain physiology and disorders

Conroy, Lindsey R.; Hawkinson, Tara R.; Young, Lyndsay E.A.; Gentry, Matthew S.; Sun, Ramon C.

doi:10.1016/j.tem.2021.09.006

Cited by 43 publications

(35 citation statements)

References 108 publications

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“…Metabolic pathways are channeled within a cell and metabolite pools can be replenished through different metabolic substrates 7 . The TCA cycle metabolite pools can be replenished from glucose, glutamine, and fatty acid metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…Neurotransmitters such as GABA, glutamate, and aspartate, can be de novo synthesized through glucose catabolism 5 . In contrast, anabolic glucose metabolism utilizes either glucose or glucose derivatives for the synthesis of lipids 6 , complex carbohydrates such as glycans 7 , chondroitin 8 and heparin sulfate biopolymers 9 , all of which are critical biomass and structural components of the brain. Given that brain glucose participates in a myriad of metabolic processes from bioenergetics to neurotransmitter and biomass production, it is difficult to decipher which downstream processes are perturbed from reduced 2-deoxyglucose uptake and are unique to disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

Juras

Webb

Young

et al. 2022

Preprint

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The brain metabolome directly connects to brain physiology and neuronal function. Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. Therefore, challenges remain to capture an accurate snapshot of the physiological brain metabolome in healthy and diseased rodent models. To overcome this barrier, we employ a high-power focused microwave for the simultaneous euthanasia and fixation of mouse brain tissue to preserve metabolite pools prior to surgical removal and dissection of brain regions. We demonstrate exhaustion of glycogen and glucose and increase in lactate production during conventional rapid brain resection prior to preservation by liquid nitrogen that is not observed with microwave fixation. Next, microwave fixation was employed to define the impact of brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple regions of the mouse brain, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the TCA cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation to study terminal brain metabolism in rodent models.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

Juras

Webb

Young

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…The remaining three pathways are significant mainly for their signal transduction cascades. The only down-regulated pathway is related to N-glycan biosynthesis, which has recently been associated with brain physiology and disorders [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

Martini

Mingardi

Carini

et al. 2023

Genes

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Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress.

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“…Consequently, the evolution of the glycome is uniquely driven by both intrinsic and extrinsic selection pressures ( 9 ). Asparagine-linked glycosylation (N-glycosylation) is critically involved in many aspects of central nervous system (CNS) biology including membrane excitability, synaptic transmission, neurite outgrowth, and neuronal plasticity ( 10 , 11 ). Recent insights have revealed that the brain N-glycome is dynamic and that its composition changes under various physiological and pathological conditions ( 12 ), yet data regarding its evolutionary trajectory are scarce.…”

Section: Main Textmentioning

confidence: 99%

Human-specific features and developmental dynamics of the brain N-glycome

Gudelj

Santpere

Sousa

et al. 2023

Preprint

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Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. Here, we performed multi-regional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry, then integrated these data with complementary glycotranscriptomic data. We found that in primates the brain N-glycome has evolved more rapidly than the underlying transcriptomic framework, providing a mechanism for generating additional diversity. We show that brain N-glycome evolution in hominids has been characterized by an increase in complexity and α(2-6)-linked N-acetylneuraminic acid along with human-specific cell type expression of key glycogenes. Finally, by comparing the prenatal and adult human brain N-glycome, we identify region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain.

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Emerging roles of N-linked glycosylation in brain physiology and disorders

Cited by 43 publications

References 108 publications

In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

Human-specific features and developmental dynamics of the brain N-glycome

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