scholarly journals A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

2021 ◽  
Vol 4 (7) ◽  
pp. e202000874
Author(s):  
Huan Du ◽  
Man Ying Wong ◽  
Tingting Zhang ◽  
Mariela Nunez Santos ◽  
Charlene Hsu ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Frontotemporal Lobar Degeneration ◽  
Microglial Activation ◽  
Nuclear Translocation ◽  
Young Male ◽  
Lysosome Biogenesis ◽  
Age Dependent ◽  
App Metabolism ◽  
Galectin 3

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer’s disease. PGRN is highly expressed in the microglia near Aβ plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aβ levels in the young male but not female mice. PGRN-deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, galectin-3, TREM2, and GPNMB, specifically near Aβ plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN-deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to Aβ fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on APP metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia.

scholarly journals A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

2021 ◽  
Author(s):  
Huan Du ◽  
Man Ying Wong ◽  
Tingting Zhang ◽  
Mariela Nunez Santos ◽  
Charlene Hsu ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Frontotemporal Lobar Degeneration ◽  
Microglial Activation ◽  
Nuclear Translocation ◽  
Young Male ◽  
Disease Mechanism ◽  
Lysosome Biogenesis ◽  
Age Dependent ◽  
Galectin 3

AbstractHaploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer’s disease (AD). PGRN is highly expressed in the microglia near Aβ plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aβ levels in the young male but not female mice. PGRN deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, Galectin-3, TREM2 and GPNMB, specifically near Aβ plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to Aβ fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on amyloid metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia, which may contribute to the disease mechanism associated with PGRN polymorphisms in AD.

scholarly journals SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and tissue homeostasis

2018 ◽  
Author(s):  
Yungang Lan ◽  
Peter M. Sullivan ◽  
Fenghua Hu
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Physiological Function ◽  
Chromosome Region ◽  
Tissue Homeostasis ◽  
Spine Density ◽  
Protein Levels ◽  
Lysosome Biogenesis ◽  
Mtorc1 Signaling ◽  
Lateral Sclerosis

AbstractThe intronic hexanucleotide expansion in the C9orf72 gene is one of the leading causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), 2 devastating neurodegenerative diseases. C9orf72 forms a heterodimer with SMCR8 (Smith-Magenis syndrome chromosome region, candidate 8) protein. However, the physiological function of SMCR8 remains to be characterized. Here we report that ablation of SMCR8 in mice results in splenomegaly with autoimmune phenotypes similar to that of C9orf72 deficiency. Furthermore, SMCR8 loss leads to a drastic decrease of C9orf72 protein levels. Many proteins involved in the macroautophagy-lysosome pathways are downregulated upon SMCR8 loss due to elevated activation of MTORC1 and AKT, which also leads to increased spine density in the Smcr8 knockout neurons. In summary, our studies demonstrate a key role of SMCR8 in regulating MTORC1 and AKT signaling and tissue homeostasis.

scholarly journals Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana M. Espinosa-Oliva ◽  
Pablo García-Miranda ◽  
Isabel María Alonso-Bellido ◽  
Ana E. Carvajal ◽  
Melania González-Rodríguez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Peripheral Inflammation ◽  
Ventral Mesencephalon ◽  
Predisposing Factor ◽  
Promising Strategy ◽  
Microglia Polarization ◽  
Galectin 3

Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states.

scholarly journals Antiviral activity of a purine synthesis enzyme reveals a key role of deamidation in regulating protein nuclear import

2019 ◽  
Vol 5 (10) ◽  
pp. eaaw7373 ◽  
Author(s):  
Junhua Li ◽  
Jun Zhao ◽  
Simin Xu ◽  
Shu Zhang ◽  
Junjie Zhang ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Nuclear Import ◽  
Nuclear Translocation ◽  
Lytic Replication ◽  
Metabolic Enzyme ◽  
Purine Synthesis ◽  
Localization Signal ◽  
Positively Charged

Protein nuclear translocation is highly regulated and crucial for diverse biological processes. However, our understanding concerning protein nuclear import is incomplete. Here we report that a cellular purine synthesis enzyme inhibits protein nuclear import via deamidation. Employing human Kaposi’s sarcoma-associated herpesvirus (KSHV) to probe the role of protein deamidation, we identified a purine synthesis enzyme, phosphoribosylformylglycinamidine synthetase (PFAS) that inhibits KSHV transcriptional activation. PFAS deamidates the replication transactivator (RTA), a transcription factor crucial for KSHV lytic replication. Mechanistically, deamidation of two asparagines flanking a positively charged nuclear localization signal impaired the binding of RTA to an importin β subunit, thus diminishing RTA nuclear localization and transcriptional activation. Finally, RTA proteins of all gamma herpesviruses appear to be regulated by PFAS-mediated deamidation. These findings uncover an unexpected function of a metabolic enzyme in restricting viral replication and a key role of deamidation in regulating protein nuclear import.

scholarly journals The role of Galectin-3 in α-synuclein-induced microglial activation

2014 ◽  
Vol 2 (1) ◽  
Author(s):  
Antonio Boza-Serrano ◽  
Juan F Reyes ◽  
Nolwen L Rey ◽  
Hakon Leffler ◽  
Luc Bousset ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Galectin 3

scholarly journals The role of Galectin-3 in ¿-synuclein-induced microglial activation

2014 ◽  
Vol 2 (1) ◽  
pp. 156 ◽  
Author(s):  
Antonio Boza-Serrano ◽  
Juan F Reyes ◽  
Nolwen L Rey ◽  
Hakon Leffler ◽  
Luc Bousset ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Galectin 3

scholarly journals Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinyin Tan ◽  
Yanqun Zheng ◽  
Daiwen Xu ◽  
Zhanfang Sun ◽  
Huan Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neurofibrillary Tangles ◽  
Microglial Activation ◽  
Amyloid Β ◽  
Review Article ◽  
Common Cause ◽  
Galectin 3

AbstractAlzheimer’s disease (AD) is the most common cause of dementia and is characterized by the deposition of extracellular aggregates of amyloid-β (Aβ), the formation of intraneuronal tau neurofibrillary tangles and microglial activation-mediated neuroinflammation. One of the key molecules involved in microglial activation is galectin-3 (Gal-3). In recent years, extensive studies have dissected the mechanisms by which Gal-3 modulates microglial activation, impacting Aβ deposition, in both animal models and human studies. In this review article, we focus on the emerging role of Gal-3 in biology and pathobiology, including its origin, its functions in regulating microglial activation and neuroinflammation, and its emergence as a biomarker in AD and other neurodegenerative diseases. These aspects are important to elucidate the involvement of Gal-3 in AD pathogenesis and may provide novel insights into the use of Gal-3 for AD diagnosis and therapy.

The role of glia in late-life depression

2012 ◽  
Vol 24 (12) ◽  
pp. 1878-1890 ◽  
Author(s):  
Matt Bennett Paradise ◽  
Sharon Linda Naismith ◽  
Louisa Margaret Norrie ◽  
Manuel Benedikt Graeber ◽  
Ian Bernard Hickie
Keyword(s):  
Microglial Activation ◽  
Gray Matter Volume ◽  
Critical Role ◽  
Late Life ◽  
Glutamate Metabolism ◽  
Late Life Depression ◽  
Subcortical Structures ◽  
Age Dependent ◽  
The Brain

ABSTRACTLate-life depression (LLD) has a complex and multifactoral etiology. There is growing interest in elucidating how glia, acting alone or as part of a glial–neuronal network, may contribute to the pathophysiology of depression. In this paper, we explore results from neuroimaging studies showing gray-matter volume loss in key frontal and subcortical structures implicated in LLD, and present the few histological studies that have examined neuronal and glial densities in these regions. Compared to results in younger people with depression, there appear to be age-dependent differences in neuronal pathology but the changes in glial pathology may be more subtle, perhaps reflecting a longer-term compensatory gliosis to earlier damage. We then consider the mechanisms by which both astrocytes and microglia may mediate and modulate neuronal dysfunction and possible degeneration in depression. These include a critical role in the response to peripheral inflammation and central microglial activation, as well as a key role in glutamate metabolism. Advances in our understanding of glia are highlighted, including the role of microglia as “electricians” of the brain and astrocytes as key communicating cells, an integral part of the tripartite synapse. Finally, implications for clinicians are discussed, including the consideration of glia as biomarkers for LLD and incorporation of glia into future therapeutic strategies.

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

2005 ◽  
Vol 289 (3) ◽  
pp. F611-F621 ◽  
Author(s):  
Carla Iacobini ◽  
Giovanna Oddi ◽  
Stefano Menini ◽  
Lorena Amadio ◽  
Carlo Ricci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Disease ◽  
Structural Parameters ◽  
Glomerular Sclerosis ◽  
Low Grade ◽  
Age Related ◽  
Age Dependent ◽  
Glomerular Lesions ◽  
Galectin 3

Aging is characterized by renal functional and structural abnormalities resembling those observed in diabetes. These changes have been related to the progressive accumulation of advanced glycation end-products (AGEs) and cumulative oxidative stress occurring in both conditions. We previously reported that galectin-3 ablation is associated with increased susceptibility to diabetes- and AGE-induced glomerulopathy, thus indicating a protective role of galectin-3 as an AGE receptor. To investigate the role of the AGE/AGE receptor pathway in the pathogenesis of age-related renal disease, we evaluated the development of glomerular lesions in aging galectin-3 knockout (KO) vs. wild-type (WT) mice and their relation to the increased AGE levels and oxidative stress characterizing the aging process. KO mice showed significantly more pronounced age-dependent increases in proteinuria, albuminuria, glomerular sclerosis, and glomerular and mesangial areas, starting at 18 mo, as well as renal extracellular matrix mRNA and protein expression, starting at 12 mo vs. age-matched WT mice. Circulating and renal AGEs, plasma isoprostane 8-epi-PGF2α levels, glomerular content of the glycoxidation and lipoxidation products Nε-carboxymethyllysine and 4-hydroxy-2-nonenal, and renal nuclear factor-κB activity also increased more markedly with age in KO than WT mice. AGE levels correlated significantly with renal functional and structural parameters. These data indicate that aging galectin-3 KO mice develop more pronounced changes in renal function and structure than coeval WT mice, in parallel with a more marked degree of AGE accumulation, oxidative stress, and associated low-grade inflammation, thus supporting the concept that the AGE/AGE receptor pathway is implicated in age-related renal disease.

Protective role of peroxiredoxin-4 in heart failure

2020 ◽  
Vol 134 (1) ◽  
pp. 71-72
Author(s):  
Naseer Ahmed ◽  
Masooma Naseem ◽  
Javeria Farooq
Keyword(s):  
Heart Failure ◽  
Cardiac Fibroblasts ◽  
Protective Role ◽  
Oxidative Stress Markers ◽  
Stress Markers ◽  
Total Antioxidant ◽  
Galectin 3 ◽  
Consequent Increase ◽  
And Oxidative Stress

Abstract Recently, we have read with great interest the article published by Ibarrola et al. (Clin. Sci. (Lond.) (2018) 132, 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

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