The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair.
Intracellular inclusions play a profound role in many neurodegenerative diseases. Here, we report that HR23B and HR23A, proteins that are involved in both DNA repair and shuttling proteins to the 26S proteasome for degradation, accumulate in neuronal inclusions in brain from a mouse model for FXTAS, as well as in brain material from HD, SCA3, SCA7, FTDP-17 and PD patients. Interestingly, HR23B did not significantly accumulate in tau-positive aggregates (neurofibrillary tangles) from AD patients while ubiquitin did. The sequestration of HR23 proteins in intracellular inclusions did not cause detectable accumulation of their stable binding partner in DNA repair, XPC. Surprisingly, no reduction in repair capacity was observed in primary human fibroblasts that overexpressed GFP-polyQ, a polypeptide that induces HR23B-positive inclusions in these transfected cells. This illustrates that impairment of the ubiquitin-proteasome system (UPS) by expanded glutamine repeats, including the sequestration of HR23B, is not affecting NER.
Bergink
Steven
S
MGC-CBG Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 1738, 3000DR, Rotterdam, The Netherlands.
Severijnen
Lies-Anne
LA
Wijgers
Nils
N
Sugasawa
Kaoru
K
Yousaf
Humaira
H
Kros
Johan M
JM
van Swieten
John
J
Oostra
Ben A
BA
Hoeijmakers
Jan H
JH
Vermeulen
Wim
W
Willemsen
Rob
R
D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004260:DNA Repair / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D010455:Peptides; C475578:Rad23a protein, mouse; C499250:Rad23b protein, mouse; D025801:Ubiquitin; D016875:tau Proteins; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex