scholarly journals Tissue-specific downregulation of EDTP suppresses polyglutamine protein aggregates and extends lifespan in Drosophila

2017 ◽  
Author(s):  
Chengfeng Xiao ◽  
Shuang Qiu ◽  
R Meldrum Robertson ◽  
Laurent Seroude
Keyword(s):  
Glial Cells ◽  
Genetic Disorder ◽  
Tyrosine Phosphatase ◽  
Protein Aggregates ◽  
Protein Aggregate ◽  
Tissue Specific ◽  
Lipid Phosphatase ◽  
Muscle Tissues ◽  
Polyq Protein ◽  
Polyglutamine Protein

ABSTRACTDrosophila egg-derived tyrosine phosphatase (EDTP, also called JUMPY) is a lipid phosphatase essential in oogenesis and muscle function in the adult stage. Although mammalian JUMPY negatively regulates autophagy, loss-of-JUMPY causes muscle dysfunction and is associated with a rare genetic disorder called centronuclear myopathy. Here we show that tissue-specific downregulation of EDTP in Drosophila non-muscle tissues, particularly glial cells, suppresses the expression of polyglutamine (polyQ) protein aggregates in the same cells and improves survival. Additionally, tissue-specific downregulation of EDTP in glial cells or motoneurons extends lifespan. We demonstrate an approach to fine-tune the expression of a disease-associated gene EDTP for the removal of polyQ protein aggregate and lifespan extension in Drosophila.

scholarly journals Drosophila egg-derived tyrosine phosphatase (EDTP): a novel target for improved survivorship to prolonged anoxia and cellular protein aggregates

2018 ◽  
Author(s):  
Chengfeng Xiao ◽  
Shuang Qiu ◽  
Xiao Li ◽  
Dan-Ju Luo ◽  
Gong-Ping Liu
Keyword(s):  
Hippocampal Neurons ◽  
Genetic Disorder ◽  
Tyrosine Phosphatase ◽  
Protein Aggregates ◽  
Cellular Protein ◽  
Muscle Performance ◽  
Homologous Gene ◽  
Sprague Dawley ◽  
Tissue Specific ◽  
Novel Approach

AbstractDrosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3-position phosphate at the inositol ring, has dual functions in the oogenesis and the muscle performance during adult stages. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) lethality in the early embryogenesis in Drosophila; (2) “jumpy” phenotype with apparently impaired motor functions; and (3) association with a rare genetic disorder called centronuclear myopathy. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissue-specific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended the lifespan; and tissue-specific downregulation of EDTP in motoneurons improved the survivorship to beta-amyloid peptides (Aβ42) and polyglutamine (polyQ) protein aggregates. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6J and APP/PS1 mice. Compared with C57BL/6J mice, APP/PS1 mice had reduced MTMR14 in the cortex but not in the hippocampus. Hippocampal expression of MTMR14 was increased and plateaued at 9-17 months compared with 2-6 months in C57BL/6J mice. Aβ42 treatment increased the expression of MTMR14 in the primarily cultured hippocampal neurons of Sprague/Dawley rats and mouse Neuro2a neuroblasts. We demonstrated a novel approach of tissue-specific manipulation of the disease-associated gene EDTP/MTMR14 for lifespan extension and the improvement of survivorship to cellular protein aggregates.

scholarly journals TheGinkgo bilobaExtract EGb 761 Modulates Proteasome Activity and Polyglutamine Protein Aggregation

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Marcel Stark ◽  
Christian Behl
Keyword(s):  
Protein Degradation ◽  
Cultured Cells ◽  
Protein Aggregates ◽  
Proteasome Activity ◽  
Protein Homeostasis ◽  
Cellular Model ◽  
Egb 761 ◽  
Polyq Protein ◽  
Polyglutamine Protein ◽  
Potential Use

The standardizedGinkgo bilobaextract EGb 761 has well-described antioxidative activities and effects on different cytoprotective signaling pathways. Consequently, a potential use of EGb 761 in neurodegenerative diseases has been proposed. A common characteristic feature of a variety of such disorders is the pathologic formation of protein aggregates, suggesting a crucial role for protein homeostasis. In this study, we show that EGb 761 increased the catalytic activity of the proteasome and enhanced protein degradation in cultured cells. We further investigated this effect in a cellular model of Huntington’s disease (HD) by employing cells expressing pathologic variants of a polyglutamine protein (polyQ protein). We show that EGb 761 affected these cells by (i) increasing proteasome activity and (ii) inducing a more efficient degradation of aggregation-prone proteins. These results demonstrate a novel activity of EGb 761 on protein aggregates by enhancing proteasomal protein degradation, suggesting a therapeutic use in neurodegenerative disorders with a disturbed protein homeostasis.

scholarly journals Effect of Copper On Bioconcentration of Benzotriazole Ultraviolet Stabilizers (BUVSs) in Common Carp (Cyprinus Carpio)

2021 ◽  
Author(s):  
Dandan Zhao ◽  
Tadiyose Girma Bekele ◽  
Hongxia Zhao
Keyword(s):  
Common Carp ◽  
Distribution Patterns ◽  
Ecological Effect ◽  
Tissue Specific ◽  
Treatment Groups ◽  
Specific Distribution ◽  
Muscle Tissues ◽  
Effect Of Copper ◽  
Depuration Rate ◽  
Kinetics Of

Abstract Benzotriazole ultraviolet stabilizers (BUVSs) have received increasing attention due to their widespread usage, ubiquitous detection and their adverse ecological effect. However, information about the bioaccumulation potential of BUVSs and their joint exposure with heavy metals remains scarce. In this study, we investigated the bioaccumulation kinetics of 6 frequently reported BUVSs in common carp under different Cu concentration for 48 d, and their tissue-specific distribution patterns (liver, kidney, gill, and muscle tissues) were also evaluated. The bioconcentration factors (BCFs) and half-lives (t1/2) in the tissues ranged from 5.73 (UV-PS) to 1076 (UV-327), and 2.19 (UV-PS) to 31.5 (UV-320) days, respectively. The tissue-specific concentration and BCF values followed the order of liver > kidney > gill > muscle with or without Cu exposure. An increase in BCF with rising Cu concentration was observed, which is caused by the decreased depuration rate (k2) in more than half of treatment groups. These results indicated that BUVSs accumulated in fish and provides important insight into the risk assessment of this group of chemicals.

scholarly journals The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

2020 ◽  
pp. jbc.RA120.014415
Author(s):  
Tapas Mukherjee ◽  
Valeria Ramaglia ◽  
Mena Abdel-Nour ◽  
Athanasia A Bianchi ◽  
Jessica Tsalikis ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Distal Colon ◽  
Ubiquitin Proteasome System ◽  
Pathological Feature ◽  
Protein Aggregate ◽  
Sensory Afferents ◽  
Cytosolic Protein ◽  
Eif2α Kinase

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response (cUPR) to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

scholarly journals The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Francisco J Piña ◽  
Maho Niwa
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mother Cell ◽  
Daughter Cell ◽  
Protein Aggregates ◽  
Cytoplasmic Protein ◽  
Protein Aggregate ◽  
Daughter Cells ◽  
Simultaneous Visualization

Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

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