Prion protein modulates glucose homeostasis by altering intracellular iron

Ashok, Ajay; Singh, Neena

doi:10.1038/s41598-018-24786-1

Cited by 33 publications

(24 citation statements)

References 68 publications

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“…In brief, apart from oxidative stress due to HIF and ROS, iron overload may induce glucose‐mediated neurodegeneration (Merelli et al, ). A role for prion in glucose uptake of the cell by altering the GLUT2 expression has also been reported, which indicates that prion can indirectly affect glucose metabolism (Ashok & Singh, ).…”

Section: Mechanisms Of T2dm‐derived Neurodegeneration In Admentioning

confidence: 96%

Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

2020

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Introduction Rigorous research in the last few years has shown that in addition to the classical mechanism of neurodegeneration, certain unconventional mechanisms may also lead to neurodegenerative disease. One of them is a widely studied metabolic disorder: type 2 diabetes mellitus (T2DM). We now have a clear understanding of glucose‐mediated neurodegeneration, mostly from studies in Alzheimer's disease (AD) models. AD is recognized to be significantly associated with hyperglycemia, even earning the term “type 3 diabetes.” Here, we review first the pathophysiology of AD, both from the perspective of classical protein accumulation, as well as the newer T2DM‐dependent mechanisms supported by findings from patients with T2DM. Secondly, we review the different pathways through which neurodegeneration is aggravated in hyperglycemic conditions taking AD as a case study. Finally, some of the current advances in AD management as a result of recent research developments in metabolic disorders‐driven neurodegeneration are also discussed. Methods Relevant literatures found from PubMed search were reviewed. Results Apart from the known causes of AD, type 2 diabetes opens a new window to the AD pathology in several ways. It is a bidirectional interaction, of which, the molecular and signaling mechanisms are recently studied. This is our attempt to connect all of them to draw a complete mechanistic explanation for the neurodegeneration in T2DM. Refer to Figure 3. Conclusion The perspective of AD as a classical neurodegenerative disease is changing, and it is now being looked at from a zoomed‐out perspective. The correlation between T2DM and AD is something observed and studied extensively. It is promising to know that there are certain advances in AD management following these studies.

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Section: Mechanisms Of T2dm‐derived Neurodegeneration In Admentioning

confidence: 96%

Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

2020

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“…Glucose intolerance develops in iron-overloaded PrP+/+ but not in PrP−/− mice, indicating that PrPC-mediated modulation of intracellular iron does influence both insulin secretion and insulin sensitivity of target organs. Thus, the PrPC protein (and possibly its abnormal variants) appear to play a role in glucose homeostasis [179]. Current research is exploring the mechanism underlying the prion-like transmission of IAPP aggregates and its possible role in T2DM [180].…”

Section: Other Infections Possibly Linked With Diabetesmentioning

confidence: 99%

The diabetes pandemic and associated infections: suggestions for clinical microbiology

Toniolo¹,

Cassani

Puggioni

et al. 2019

Reviews in Medical Microbiology

127

124

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There are 425 million people with diabetes mellitus in the world. By 2045, this figure will grow to over 600 million. Diabetes mellitus is classified among noncommunicable diseases. Evidence points to a key role of microbes in diabetes mellitus, both as infectious agents associated with the diabetic status and as possible causative factors of diabetes mellitus. This review takes into account the different forms of diabetes mellitus, the genetic determinants that predispose to type 1 and type 2 diabetes mellitus (especially those with possible immunologic impact), the immune dysfunctions that have been documented in diabetes mellitus. Common infections occurring more frequently in diabetic vs. nondiabetic individuals are reviewed. Infectious agents that are suspected of playing an etiologic/triggering role in diabetes mellitus are presented, with emphasis on enteroviruses, the hygiene hypothesis, and the environment. Among biological agents possibly linked to diabetes mellitus, the gut microbiome, hepatitis C virus, and prion-like protein aggregates are discussed. Finally, preventive vaccines recommended in the management of diabetic patients are considered, including the bacillus calmette-Guerin vaccine that is being tested for type 1 diabetes mellitus. Evidence supports the notion that attenuation of immune defenses (both congenital and secondary to metabolic disturbances as well as to microangiopathy and neuropathy) makes diabetic people more prone to certain infections. Attentive microbiologic monitoring of diabetic patients is thus recommendable. As genetic predisposition cannot be changed, research needs to identify the biological agents that may have an etiologic role in diabetes mellitus, and to envisage curative and preventive ways to limit the diabetes pandemic.

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“…Immunohistochemistry was performed as described 37 (antibody list in Supplementary Table S2). Stained sections were mounted and imaged with Leica inverted microscope (DMi8).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Protein lysates were fractionated by SDS-PAGE and analyzed by Western blotting as described. 15,16,33,37 Proteins of interest were visualized by probing with specific antibodies (antibody list in Supplementary Table S2). RT-PCR was carried out as described earlier 15 (primer list in Supplementary Table S3).…”

Section: Sds-page Western Blotting and Rt-pcrmentioning

confidence: 99%

TGFβ2-Hepcidin Feed-Forward Loop in the Trabecular Meshwork Implicates Iron in Glaucomatous Pathology

Ashok

Chaudhary

Kritikos

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Elevated levels of transforming-growth-factor (TGF)-β2 in the trabecular meshwork (TM) and aqueous humor are associated with primary open-angle glaucoma (POAG). The underlying mechanism includes alteration of extracellular matrix homeostasis through Smad-dependent and independent signaling. Smad4, an essential co-Smad, upregulates hepcidin, the master regulator of iron homeostasis. Here, we explored whether TGF-β2 upregulates hepcidin, implicating iron in the pathogenesis of POAG. METHODS. Primary human TM cells and human and bovine ex vivo anterior segment organ cultures were exposed to bioactive TGF-β2, hepcidin, heparin (a hepcidin antagonist), or N-acetyl carnosine (an antioxidant), and the change in the expression of hepcidin, ferroportin, ferritin, and TGF-β2 was evaluated by semiquantitative RT-PCR, Western blotting, and immunohistochemistry. Increase in reactive oxygen species (ROS) was quantified with dihydroethidium, an ROS-sensitive dye. RESULTS. Primary human TM cells and bovine TM tissue synthesize hepcidin locally, which is upregulated by bioactive TGF-β2. Hepcidin downregulates ferroportin, its downstream target, increasing ferritin and iron-catalyzed ROS. This causes reciprocal upregulation of TGF-β2 at the transcriptional and translational levels. Heparin downregulates hepcidin, and reduces TGF-β2-mediated increase in ferritin and ROS. Notably, both heparin and N-acetyl carnosine reduce TGF-β2-mediated reciprocal upregulation of TGF-β2. CONCLUSIONS. The above observations suggest that TGF-β2 and hepcidin form a selfsustained feed-forward loop through iron-catalyzed ROS. This loop is partially disrupted by a hepcidin antagonist and an anti-oxidant, implicating iron and ROS in TGF-β2mediated POAG. We propose that modification of currently available hepcidin antagonists for ocular use may prove beneficial for the therapeutic management of TGF-β2-associated POAG.

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Prion protein modulates glucose homeostasis by altering intracellular iron

Cited by 33 publications

References 68 publications

Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

The diabetes pandemic and associated infections: suggestions for clinical microbiology

TGFβ2-Hepcidin Feed-Forward Loop in the Trabecular Meshwork Implicates Iron in Glaucomatous Pathology

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