scholarly journals Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

2020 ◽  
Vol 139 (4) ◽  
pp. 735-771 ◽  
Author(s):  
Isidro Ferrer ◽  
Pol Andrés-Benito ◽  
Maria Victoria Zelaya ◽  
Maria Elena Erro Aguirre ◽  
Margarita Carmona ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Age Of Onset ◽  
Uncoupling Protein ◽  
Glutamate Transporter ◽  
Wild Type ◽  
Mitochondrial Uncoupling ◽  
Altered Expression ◽  
Mitochondrial Uncoupling Protein ◽  
Coiled Bodies ◽  
Globular Glial Tauopathy

AbstractGlobular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.

scholarly journals Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus

2016 ◽  
Vol 310 (7) ◽  
pp. C558-C567 ◽  
Author(s):  
Francesca Urbano ◽  
Agnese Filippello ◽  
Antonino Di Pino ◽  
Davide Barbagallo ◽  
Stefania Di Mauro ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
High Glucose ◽  
Cell Function ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Mitochondrial Uncoupling ◽  
Altered Expression ◽  
Atp Production ◽  
Mitochondrial Uncoupling Protein ◽  
Diabetes Patients

Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP+) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.

scholarly journals Effects of Mitochondrial Uncoupling Protein 2 Inhibition by Genipin in Human Cumulus Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Hongshan Ge ◽  
Fan Zhang ◽  
Dan Shan ◽  
Hua Chen ◽  
Xiaona Wang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Uncoupling Protein ◽  
Physiological Role ◽  
Cumulus Cells ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein ◽  
Cultural Medium ◽  
Cellular Autophagy ◽  
Significant Difference ◽  
Active Caspase

UCP2 plays a physiological role by regulating mitochondrial biogenesis, maintaining energy balance, ROS elimination, and regulating cellular autophagy in numerous tissues. But the exact roles of UCP2 in cumulus cells are still not clear. Genipin, a special UCP2 inhibitor, was added into the cultural medium to explore the roles of UCP2 in human cumulus cells. There were no significant differences in ATP and mitochondrial membrane potential levels in cumulus cells from UCP2 inhibiting groups as compared with the control. The levels of ROS and Mn-SOD were markedly elevated after UCP2 inhibited Genipin. However, the ratio of reduced GSH to GSSG significantly declined after treatment with Genipin. UCP2 inhibition by Genipin also resulted in obvious increase in the active caspase-3, which accompanied the decline of caspase-3 mRNA. The level of progesterone in culture medium declined obviously after Genipin treatment. But there was no significant difference in estradiol concentrations. This study indicated that UCP2 is expressed in human cumulus cells and plays important roles on mediate ROS production, apoptotic process, and steroidogenesis, suggesting UCP2 may be involved in regulation of follicle development and oocyte maturation and quality.

scholarly journals Mitochondrial Hormesis in PancreaticβCells: Does Uncoupling Protein 2 Play a Role?

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Ning Li ◽  
Suzana Stojanovski ◽  
Pierre Maechler
Keyword(s):  
Stress Responses ◽  
Defense Mechanisms ◽  
Defense Mechanism ◽  
Cell Function ◽  
Uncoupling Protein ◽  
Glucose Sensing ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein ◽  
Cellular Stresses ◽  
Excessive Nutrients

In pancreaticβcells, mitochondrial metabolism translates glucose sensing into signals regulating insulin secretion. Chronic exposure ofβcells to excessive nutrients, namely, glucolipotoxicity, impairsβ-cell function. This is associated with elevated ROS production from overstimulated mitochondria. Mitochondria are not only the major source of cellular ROS, they are also the primary target of ROS attacks. The mitochondrial uncoupling protein UCP2, even though its uncoupling properties are debated, has been associated with protective functions against ROS toxicity. Hormesis, an adaptive response to cellular stresses, might contribute to the protection againstβ-cell death, possibly limiting the development of type 2 diabetes. Mitochondrial hormesis, or mitohormesis, is a defense mechanism observed in ROS-induced stress-responses by mitochondria. Inβcells, mitochondrial damages induced by sublethal exogenous H2O2can induce secondary repair and defense mechanisms. In this context, UCP2 is a marker of mitohormesis, being upregulated following stress conditions. When overexpressed in nonstressed naïve cells, UCP2 confers resistance to oxidative stress. Whether treatment with mitohormetic inducers is sufficient to restore or ameliorate secretory function ofβcells remains to be determined.

scholarly journals Mitochondrial uncoupling protein 2 (UCP2), but not UCP3, is sensitive to oxygen concentration in cells

2020 ◽  
Author(s):  
Karolina E. Hilse ◽  
Anne Rupprecht ◽  
Kristopher Ford ◽  
Olena Andrukhova ◽  
Reinhold Erben ◽  
...  
Keyword(s):  
Stem Cell ◽  
Oxygen Concentration ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Mitochondrial Uncoupling ◽  
Homologous Proteins ◽  
Mitochondrial Uncoupling Protein ◽  
Pathological Conditions

AbstractOne of the important hallmarks of cardiovascular disease is mitochondrial dysfunction, which results in abnormal energy metabolism and increased ROS production in cardiomyocytes. Members of the mitochondrial uncoupling protein family, UCP2 and UCP3, are thought to be beneficial by reducing ROS due to mild uncoupling. More recent hypotheses suggest the involvement of both proteins in cell metabolism by the transport of yet unknown substrates. The protein expression pattern under physiological and pathological conditions is an important clue for the evaluation of UCP2/UCP3 function, however, there is still no consensus about it. Previously, we demonstrated that only UCP3 is present in the adult murine heart under physiological conditions and correlated it with the predominant use of fatty acids for oxidation. In contrast, UCP2 was found only in very young (stem cell – like) cardiomyocytes, that rely mostly on glycolysis. Here, we employed three different models (ex vivo heart ischemia-reperfusion model, myocardial infarction model, and embryonic stem cell differentiation into cardiomyocytes under hypoxic conditions) to evaluate the abundance of both proteins under ischemia and hypoxia conditions. We found that (i) oxygen shortage or bursts did not influence UCP3 levels in the heart and ii) UCP2 was not present in healthy, ischemic, or re-perfused hearts. However, (iii) UCP2 was sensitive to the oxygen concentration in stem cells, in which UCP2 is normally expressed. These results further support the idea, that two highly homologous proteins – UCP2 and UCP3 – are abundant in different cells and tissues, and differently regulated under physiological and pathological conditions.

scholarly journals Mitochondrial Uncoupling protein‐2 regulates NLRP3 inflammasome

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Rajan babu Venugopal ◽  
Ruan Rollin Cox ◽  
prasanna Tamarappu Parthasarathy ◽  
Richard F Lockey ◽  
Narasaiah Kolliputi
Keyword(s):  
Nlrp3 Inflammasome ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein
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