Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

Tjakko J. van Ham; Mats A. Holmberg; Annemieke T. van der Goot; Eva Teuling; Moises Garcia-Arencibia; Hyun-eui Kim; Deguo Du; Karen L. Thijssen; Marit Wiersma; Rogier Burggraaff; Petra van Bergeijk; Jeroen van Rheenen; G. Jerre van Veluw; Robert M. W. Hofstra; David C. Rubinsztein; Ellen A. A. Nollen

doi:10.1016/j.cell.2010.07.020

Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

Tjakko J. van Ham, Mats A. Holmberg, Annemieke T. van der Goot, Eva Teuling, Moises Garcia-Arencibia, Hyun-eui Kim, Deguo Du, Karen L. Thijssen, Marit Wiersma, Rogier Burggraaff, Petra van Bergeijk, Jeroen van Rheenen, G. Jerre van Veluw, Robert M. W. Hofstra, David C. Rubinsztein, Ellen A. A. Nollen^*

^*Corresponding author for this work

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

107 Citations (Scopus)

Abstract

Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.

Original language	English
Pages (from-to)	601-612
Number of pages	12
Journal	Cell
Volume	142
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2010.07.020
Publication status	Published - 20-Aug-2010

Keywords

INCLUSION-BODY FORMATION
HEAT-SHOCK FACTOR
CAENORHABDITIS-ELEGANS
HUNTINGTONS-DISEASE
POLYGLUTAMINE EXPANSIONS
MOLECULAR CHAPERONES
PROTEIN-DEGRADATION
CELLULAR TOXICITY
MUTANT HUNTINGTIN
QUALITY-CONTROL

Access to Document

10.1016/j.cell.2010.07.020

Handle.net

Persistent link

Cite this

van Ham, T. J., Holmberg, M. A., van der Goot, A. T., Teuling, E., Garcia-Arencibia, M., Kim, H., Du, D., Thijssen, K. L., Wiersma, M., Burggraaff, R., van Bergeijk, P., van Rheenen, J., van Veluw, G. J., Hofstra, R. M. W., Rubinsztein, D. C., & Nollen, E. A. A. (2010). Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity. Cell, 142(4), 601-612. https://doi.org/10.1016/j.cell.2010.07.020

@article{4f7c6af2c2be46a6ba0d992d59597e5e,

title = "Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity",

abstract = "Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.",

keywords = "INCLUSION-BODY FORMATION, HEAT-SHOCK FACTOR, CAENORHABDITIS-ELEGANS, HUNTINGTONS-DISEASE, POLYGLUTAMINE EXPANSIONS, MOLECULAR CHAPERONES, PROTEIN-DEGRADATION, CELLULAR TOXICITY, MUTANT HUNTINGTIN, QUALITY-CONTROL",

author = "{van Ham}, {Tjakko J.} and Holmberg, {Mats A.} and {van der Goot}, {Annemieke T.} and Eva Teuling and Moises Garcia-Arencibia and Hyun-eui Kim and Deguo Du and Thijssen, {Karen L.} and Marit Wiersma and Rogier Burggraaff and {van Bergeijk}, Petra and {van Rheenen}, Jeroen and {van Veluw}, {G. Jerre} and Hofstra, {Robert M. W.} and Rubinsztein, {David C.} and Nollen, {Ellen A. A.}",

year = "2010",

month = aug,

day = "20",

doi = "10.1016/j.cell.2010.07.020",

language = "English",

volume = "142",

pages = "601--612",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

}

van Ham, TJ, Holmberg, MA, van der Goot, AT, Teuling, E, Garcia-Arencibia, M, Kim, H, Du, D, Thijssen, KL, Wiersma, M, Burggraaff, R, van Bergeijk, P, van Rheenen, J, van Veluw, GJ, Hofstra, RMW, Rubinsztein, DC & Nollen, EAA 2010, 'Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity', Cell, vol. 142, no. 4, pp. 601-612. https://doi.org/10.1016/j.cell.2010.07.020

TY - JOUR

T1 - Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

AU - van Ham, Tjakko J.

AU - Holmberg, Mats A.

AU - van der Goot, Annemieke T.

AU - Teuling, Eva

AU - Garcia-Arencibia, Moises

AU - Kim, Hyun-eui

AU - Du, Deguo

AU - Thijssen, Karen L.

AU - Wiersma, Marit

AU - Burggraaff, Rogier

AU - van Bergeijk, Petra

AU - van Rheenen, Jeroen

AU - van Veluw, G. Jerre

AU - Hofstra, Robert M. W.

AU - Rubinsztein, David C.

AU - Nollen, Ellen A. A.

PY - 2010/8/20

Y1 - 2010/8/20

N2 - Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.

AB - Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.

KW - INCLUSION-BODY FORMATION

KW - HEAT-SHOCK FACTOR

KW - CAENORHABDITIS-ELEGANS

KW - HUNTINGTONS-DISEASE

KW - POLYGLUTAMINE EXPANSIONS

KW - MOLECULAR CHAPERONES

KW - PROTEIN-DEGRADATION

KW - CELLULAR TOXICITY

KW - MUTANT HUNTINGTIN

KW - QUALITY-CONTROL

U2 - 10.1016/j.cell.2010.07.020

DO - 10.1016/j.cell.2010.07.020

M3 - Article

C2 - 20723760

SN - 0092-8674

VL - 142

SP - 601

EP - 612

JO - Cell

JF - Cell

IS - 4

ER -

Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this