Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity.
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.
van Ham
Tjakko J
TJ
Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Holmberg
Mats A
MA
van der Goot
Annemieke T
AT
Teuling
Eva
E
Garcia-Arencibia
Moises
M
Kim
Hyun-eui
HE
Du
Deguo
D
Thijssen
Karen L
KL
Wiersma
Marit
M
Burggraaff
Rogier
R
van Bergeijk
Petra
P
van Rheenen
Jeroen
J
Jerre van Veluw
G
G
Hofstra
Robert M W
RM
Rubinsztein
David C
DC
Nollen
Ellen A A
EA
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; C552054:MOAG-4 protein, C elegans; D009419:Nerve Tissue Proteins; D010455:Peptides; D011506:Proteins; C114841:SERF1A protein, human; C552053:SERF2 protein, human; D051844:alpha-Synuclein; C097188:polyglutamine