TY - JOUR
T1 - The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair
AU - Bergink, Steven
AU - Severijnen, Lies Anne
AU - Wijgers, Nils
AU - Sugasawa, Kaoru
AU - Yousaf, Humaira
AU - Kros, Johan M.
AU - van Swieten, John
AU - Oostra, Ben A.
AU - Hoeijmakers, Jan H.
AU - Vermeulen, Wim
AU - Willemsen, Rob
N1 - Funding Information:
We thank Dr. R. de Vos for providing patient material and Dr. F. van Leeuwen for providing the polyQ-GFP construct. Ruud Koppenol and Tom de Vries Lentsch are acknowledged for their excellent photography. This work was supported by grants of The Netherlands Organization for Scientific Research (NWO: 014-90-001) (SB and HY), 912-03-12/917-46-364, NKB EMCR2002-2703 (WV), NFXF (RW) and Prinses Beatrix fonds (RW). The authors declare that there is no conflict of interest.
PY - 2006/9
Y1 - 2006/9
N2 - 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.
AB - 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.
KW - DNA repair
KW - HR23B
KW - Inclusions
KW - Neurodegenerative disorders
KW - Ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=33747166728&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2006.06.005
DO - 10.1016/j.nbd.2006.06.005
M3 - Article
C2 - 16860562
AN - SCOPUS:33747166728
SN - 0969-9961
VL - 23
SP - 708
EP - 716
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -