scholarly journals E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity

2008 ◽  
Vol 283 (12) ◽  
pp. 7648-7656 ◽  
Author(s):  
Amit Mishra ◽  
Priyanka Dikshit ◽  
Sudarshana Purkayastha ◽  
Jaiprakash Sharma ◽  
Nobuyuki Nukina ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Proteasomal Degradation ◽  
Polyglutamine Protein

scholarly journals Inhibition of Polyglutamine Protein Aggregation and Cell Death by Novel Peptides Identified by Phage Display Screening

2000 ◽  
Vol 275 (14) ◽  
pp. 10437-10442 ◽  
Author(s):  
Yoshitaka Nagai ◽  
Timothy Tucker ◽  
Hongzu Ren ◽  
Daniel J. Kenan ◽  
Barry S. Henderson ◽  
...  
Keyword(s):  
Cell Death ◽  
Phage Display ◽  
Protein Aggregation ◽  
Polyglutamine Protein

scholarly journals Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

2015 ◽  
Vol 35 (10) ◽  
pp. 1754-1762 ◽  
Author(s):  
Sangjune Kim ◽  
Dohyun Lee ◽  
Juhyun Lee ◽  
Haengjin Song ◽  
Hyo-Jin Kim ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Ubiquitin Proteasome System ◽  
Mutant Protein ◽  
Critical Pathway ◽  
Interacting Protein ◽  
Protein Levels ◽  
Functional Regulation ◽  
The Stability ◽  
And Function ◽  
Polyglutamine Protein

Molecular chaperones monitor the proper folding of misfolded proteins and function as the first line of defense against mutant protein aggregation in neurodegenerative diseases. The eukaryotic chaperonin TRiC is a potent suppressor of mutant protein aggregation and toxicity in early stages of disease progression. Elucidation of TRiC functional regulation will enable us to better understand the pathological mechanisms of neurodegeneration. We have previously shown that vaccinia-related kinase 2 (VRK2) downregulates TRiC protein levels through the ubiquitin-proteasome system by recruiting the E3 ligase COP1. However, although VRK2 activity was necessary in TRiC downregulation, the phosphorylated substrate was not determined. Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr680, Thr727, and Ser745residues. Impaired USP25 deubiquitinating activity after VRK2-mediated phosphorylation may be a critical pathway in TRiC protein destabilization.

scholarly journals Ubiquitin conjugating enzymes participate in polyglutamine protein aggregation

2007 ◽  
Vol 8 (1) ◽  
pp. 32 ◽  
Author(s):  
Rebecca A Howard ◽  
Pratima Sharma ◽  
Connie Hajjar ◽  
Kim A Caldwell ◽  
Guy A Caldwell ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Conjugating Enzymes ◽  
Ubiquitin Conjugating Enzymes ◽  
Polyglutamine Protein

scholarly journals A discontinuous Galerkin model for fluorescence loss in photobleaching of intracellular polyglutamine protein aggregates

2018 ◽  
Author(s):  
Christian Valdemar Hansen ◽  
Hans J Schroll ◽  
Daniel Wüstner
Keyword(s):  
Protein Aggregation ◽  
Discontinuous Galerkin ◽  
Computing Time ◽  
Diffusion Constant ◽  
Protein Aggregates ◽  
Computational Method ◽  
Transport Parameters ◽  
Cellular Models ◽  
Polyq Diseases ◽  
Polyglutamine Protein

Background: Intracellular phase separation and aggregation of proteins with extended poly-glutamine (polyQ) stretches are hallmarks of various age-associated neurodegenerative diseases. Progress in our understanding of such processes heavily relies on quantitative fluorescence imaging of suitably tagged proteins. Fluorescence loss in photobleaching (FLIP) is particularly well-suited to study the dynamics of protein aggregation in cellular models of Chorea Huntington and other polyQ diseases, as FLIP gives access to the full spatio-temporal profile of intensity changes in the cell geometry. In contrast to other methods, also dim aggregates become visible during time evolution of fluorescence loss in cellular compartments. However, methods for computational analysis of FLIP data are sparse, and transport models for estimation of transport and diffusion parameters from experimental FLIP sequences are missing. Results: In this paper, we present a computational method for analysis of FLIP imaging experiments of intracellular polyglutamine protein aggregates also called inclusion bodies (IBs). By this method, we are able to determine the diffusion constant and nuclear membrane permeability coefficients of polyQ proteins as well as the exchange rates between aggregates and the cytoplasm. Our method is based on a reaction-diffusion multi-compartment model defined on a mesh obtained by segmentation of the cell images from the FLIP sequence. The discontinuous Galerkin (DG) method is used for numerical implementation of our model in FEniCS, which greatly reduces the computing time. The method is applied to representative experimental FLIP sequences, and consistent estimates of all transport parameters are obtained. Conclusions: By directly estimating the transport parameters from live-cell image sequences using our new computational FLIP approach surprisingly fast exchange dynamics of mutant Huntingtin between cytoplasm and dim IBs could be revealed. This is likely relevant also for other polyQ diseases. Thus, our method allows for quantifying protein dynamics at different stages of the protein aggregation process in cellular models of neurodegeneration.

SynB3 conjugated QBP1 passes blood-brain barrier models and inhibits polyQ protein aggregation

2021 ◽  
Vol 29 ◽  
Author(s):  
Lingyan Zuo ◽  
Weiqian Li ◽  
Jifang Shi ◽  
Yingzhen Su ◽  
Hongyan Shuai ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Blood Brain Barrier ◽  
Cell Penetrating Peptides ◽  
Brain Barrier ◽  
Polyglutamine Diseases ◽  
Binding Peptide ◽  
Blood Brain ◽  
Cell Penetrating ◽  
Pass Through ◽  
Polyglutamine Protein

Background: Polyglutamine diseases are degenerative diseases in the central nervous system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide 1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect could be improved by increasing the rate of membrane penetration. Objectives: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation of polyglutamine proteins. Methods: n order to investigate the toxic effects, we constructed a novel stable inducible PC12 cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively, and we tested their capabilities to pass through a Trans-well system and subsequently studied the counteractive effects on polyglutamine protein aggregation. Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine-expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins, for example, β-Amyloid. Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine inclusions, thus SynB3 conjugated polyglutamine binding peptide 1 could be considered as a therapeutic candidate for polyglutamine diseases.

scholarly journals Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity

2002 ◽  
Vol 99 (Supplement 4) ◽  
pp. 16412-16418 ◽  
Author(s):  
H. Sakahira ◽  
P. Breuer ◽  
M. K. Hayer-Hartl ◽  
F. U. Hartl
Keyword(s):  
Protein Aggregation ◽  
Molecular Chaperones ◽  
Polyglutamine Protein

scholarly journals Impaired Cutinase Secretion in Saccharomyces cerevisiae Induces Irregular Endoplasmic Reticulum (ER) Membrane Proliferation, Oxidative Stress, and ER-Associated Degradation

2002 ◽  
Vol 68 (5) ◽  
pp. 2155-2160 ◽  
Author(s):  
C. M. J. Sagt ◽  
W. H. Müller ◽  
L. van der Heide ◽  
J. Boonstra ◽  
A. J. Verkleij ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Protein Aggregation ◽  
Fold Increase ◽  
Proteasomal Degradation ◽  
Wild Type ◽  
Unfolded Protein ◽  
Protein Response ◽  
And Oxidative Stress

ABSTRACT Impaired secretion of the hydrophobic CY028 cutinase invokes an unfolded protein response (UPR) in Saccharomyces cerevisiae cells. Here we show that the UPR in CY028-expressing S. cerevisiae cells is manifested as an aberrant morphology of the endoplasmic reticulum (ER) and as extensive membrane proliferation compared to the ER morphology and membrane proliferation of wild-type CY000-producing S. cerevisiae cells. In addition, we observed oxidative stress, which resulted in a 21-fold increase in carbonylated proteins in the CY028-producing S. cerevisiae cells. Moreover, CY028-producing S. cerevisiae cells use proteasomal degradation to reduce the amount of accumulated CY028 cutinase, thereby attenuating the stress invoked by CY028 cutinase expression. This proteasomal degradation occurs within minutes and is characteristic of ER-associated degradation (ERAD). Our results clearly show that impaired secretion of the heterologous, hydrophobic CY028 cutinase in S. cerevisiae cells leads to protein aggregation in the ER, aberrant ER morphology and proliferation, and oxidative stress, as well as a UPR and ERAD.

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