Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells

Seo, Hyemyung; Sonntag, Kai‐Christian; Kim, Woori; Cattaneo, Elena; Isacson, Ole

doi:10.1371/journal.pone.0000238

Cited by 118 publications

(85 citation statements)

References 51 publications

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“…REGγ has been reported to be expressed within neurons in the brain (Seo et al, 2007). We found by immunostaining that REGγ is expressed in various brain regions, with relatively high levels in the cortex and hippocampus (see Supplementary Figure 3a).…”

Section: Gsk3β Is Regulated By Regγ In Vitro and In Vivomentioning

confidence: 66%

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

Meng

Dong

et al. 2015

Neuropsychopharmacol

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GSK3β regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3β protein stability remain ambiguous. REGγ, an important proteasome activator for ubiquitin-independent protein degradation, has been shown to degrade certain intact proteins and is involved in the regulation of important biological processes. Here we demonstrate that REGγ promotes the degradation of GSK3β protein in vitro and in vivo. With increased GSK3β activity, REGγ knockout (REGγ − / − ) mice exhibit late-onset sensorimotor gating and cognitive deficiencies including decreased working memory, hyperlocomotion, increased stereotype, defective prepulse inhibition (PPI), and disability in nest building, at the age of 8 months or older. Inhibition of GSK3β rescued the compromised PPI phenotypes and working memory deficiency in the knockout mice. Also, we found an age-dependent decrease in the trypsin-like proteasomal activity in REGγ − / − mice brains, which may be reflective of a lack of degradation of GSK3β. Collectively, our findings reveal a novel regulatory pathway in which the REGγ-proteasome controls the steady-state level of GSK3β protein. Dysfunction in this noncanonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice.

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Section: Gsk3β Is Regulated By Regγ In Vitro and In Vivomentioning

confidence: 66%

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

Meng

Dong

et al. 2015

Neuropsychopharmacol

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“…Increased levels of Rpn6 in C. elegans or Rpn11 in D. melanogaster reduce toxic aggregates and suppress expanded PolyQ-induced neurodegeneration in HD models 54,141 . Increased expression of PA28g improves cell survival in a cellular model of HD 152 . Modulation of autophagy has beneficial effects on neurodegenerative diseases.…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

The role of protein clearance mechanisms in organismal ageing and age-related diseases

2014

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“…This may lead to the accumulation of pathological proteins, cell dysfunction and its death. It is known that the ubiquitination of the protein and its proteasomal degradation requires energy stored in ATP, which indicates that the deposition of aggregated proteins may be the result of a decrease in ATP synthesis due to a defect in mitochondrial respiratory chain [29,27].…”

Section: Disorders Of the Ubiquitin-proteasomal Pathwaymentioning

confidence: 99%

“…Może prowadzić do akumulacji patologicznych białek, dysfunkcji komórki, a następnie jej śmierci. Wiadomo, że do ubikwitynacji białka, jak i do jego degradacji w proteasomach, potrzebna jest energia magazynowana w ATP, co daje możliwość, że odkładanie się agregatów białkowych może być spowodowane spadkiem syntezy ATP na skutek defektu mitochondrialnych łańcuchów oddechowych [29,27].…”

Section: Ubiwiktynacjaunclassified

Mechanisms promoting and inhibiting the process of proteasomal degradation of cells

Pedrycz

Kramkowska

2016

Current Problems of Psychiatry

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Defects in the process of degradation of unneeded cellular proteins underlie many diseases. This article discusses one of the most important systems of removal of abnormal proteins. It describes the process of ubiquitination of proteins for proteasome degradation. It also describes the structure of the 26S and 20S proteasomes and the mechanism of ubiquitin-proteasome system. Proteasome proteolytic system is highly specialized and organized. Protease-proteasome 26S is particularly important for proper cell functioning. It recognizes and degrades marked proteins. Inhibition of proteasome pathway leads to cell cycle arrest and apoptosis.Efficient degradation of cellular proteins by UPS (the ubiquitin -proteasome system) -is important for signal transduction, transcriptional regulation, response to stress and the activity control of cell receptors.The development of many diseases has its origin in the dysfunction of the UPS route. This group includes diseases such as cancer, neurodegenerative disorders, immune-mediated diseases and infectious diseases. Development of effective methods for pharmacological intervention in the functioning of this system has become a great challenge. The use of specific, low molecular-weight proteasome inhibitors and enzymes catalyzing the ubiquitination gives hope for new, targeted therapies.Keywords: proteasome, lysosome, UPS -ubiquitin-proteasome system Streszczenie Zaburzenia procesu degradacji nieużytecznych komórkowych białek leżą u podstaw wielu chorób. Niniejszy artykuł omawia jeden z najważniejszych systemów usuwających nieprawidłowe białka. Opisany został proces ubikwitynacji białek przeznaczonych do degradacji proteasomalnej. Przedstawiona została budowa proteasomów 26S, 20S oraz mechanizm działania systemu ubikwitynaproteasom. Proteasomalny system proteolityczny jest systemem wysoce wyspecjalizowanym i zorganizowanym. Dla prawidłowego funkcjonowania komórki istotne znaczenie ma szczególnie proteaza -proteasom 26S. To ona rozpoznaje i degraduje zaznaczone białka. Inhibicja szlaku proteasomów prowadzi do zatrzymania cyklu komórkowego i apoptozy.Sprawna degradacja białek komórkowych przez szlak UPS (ubikwityna-proteasom) jest istotna dla transdukcji sygnału, regulacji transkrypcji, odpowiedzi na stres oraz kontroli czynności receptorów komórkowych.Rozwój wielu chorób ma swoje podłoże w dysfunkcji szlaku UPS. Zaliczamy do tej grupy takie choroby jak: nowotwory, zaburzenia neurodegeneracyjne, o podłożu immunologicznym i infekcyjnym. Opracowanie metod farmakologicznej interwencji w funkcjonowanie tego układu staje się wielkim wyzwaniem. Zastosowanie swoistych, niskocząsteczkowych inhibitorów proteasomu i enzymów katalizujących ubikwitynację daje nadzieję na nowe, celowane terapie.Słowa kluczowe: proteasom, lizosom, UPS -system ubiwiktyna-proteasom

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Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells

Cited by 118 publications

References 51 publications

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

The role of protein clearance mechanisms in organismal ageing and age-related diseases

Mechanisms promoting and inhibiting the process of proteasomal degradation of cells

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