Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases

Remko de Pril; David F Fischer; Marion L C Maat-Schieman; Barbara Hobo; Rob A I de Vos; Ewout R Brunt; Elly M Hol; Raymund A C Roos; Fred W van Leeuwen

doi:10.1093/hmg/ddh188

Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases

Remko de Pril, David F Fischer, Marion L C Maat-Schieman, Barbara Hobo, Rob A I de Vos, Ewout R Brunt, Elly M Hol, Raymund A C Roos, Fred W van Leeuwen

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.

Original language	English
Pages (from-to)	1803-13
Number of pages	11
Journal	Human Molecular Genetics
Volume	13
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddh188
Publication status	Published - 15 Aug 2004

Keywords

Apoptosis
Blotting, Western
Brain
Cell Survival
Cloning, Molecular
DNA, Complementary
Fluorescent Antibody Technique
Heredodegenerative Disorders, Nervous System
Humans
Immunohistochemistry
Inclusion Bodies
Peptides
Plasmids
Transfection
Tumor Cells, Cultured
Ubiquitin
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

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title = "Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases",

abstract = "Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.",

keywords = "Apoptosis, Blotting, Western, Brain, Cell Survival, Cloning, Molecular, DNA, Complementary, Fluorescent Antibody Technique, Heredodegenerative Disorders, Nervous System, Humans, Immunohistochemistry, Inclusion Bodies, Peptides, Plasmids, Transfection, Tumor Cells, Cultured, Ubiquitin, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't",

author = "{de Pril}, Remko and Fischer, {David F} and Maat-Schieman, {Marion L C} and Barbara Hobo and {de Vos}, {Rob A I} and Brunt, {Ewout R} and Hol, {Elly M} and Roos, {Raymund A C} and {van Leeuwen}, {Fred W}",

year = "2004",

month = aug,

day = "15",

doi = "10.1093/hmg/ddh188",

language = "English",

volume = "13",

pages = "1803--13",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

TY - JOUR

T1 - Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases

AU - de Pril, Remko

AU - Fischer, David F

AU - Maat-Schieman, Marion L C

AU - Hobo, Barbara

AU - de Vos, Rob A I

AU - Brunt, Ewout R

AU - Hol, Elly M

AU - Roos, Raymund A C

AU - van Leeuwen, Fred W

PY - 2004/8/15

Y1 - 2004/8/15

N2 - Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.

AB - Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.

KW - Apoptosis

KW - Blotting, Western

KW - Brain

KW - Cell Survival

KW - Cloning, Molecular

KW - DNA, Complementary

KW - Fluorescent Antibody Technique

KW - Heredodegenerative Disorders, Nervous System

KW - Humans

KW - Immunohistochemistry

KW - Inclusion Bodies

KW - Peptides

KW - Plasmids

KW - Transfection

KW - Tumor Cells, Cultured

KW - Ubiquitin

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/hmg/ddh188

DO - 10.1093/hmg/ddh188

M3 - Article

C2 - 15198995

SN - 0964-6906

VL - 13

SP - 1803

EP - 1813

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases

Abstract

Keywords

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