Increased expression of p62/SQSTM1 in prion diseases and its association with pathogenic prion protein

被引:35
作者
Homma, Takujiro [1 ]
Ishibashi, Daisuke [1 ]
Nakagaki, Takehiro [1 ]
Satoh, Katsuya [1 ]
Sano, Kazunori [1 ]
Atarashi, Ryuichiro [1 ,2 ]
Nishida, Noriyuki [1 ]
机构
[1] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Microbiol & Immunol, Nagasaki 8528523, Japan
[2] Nagasaki Univ, Res Ctr Genom Instabil & Carcinogenesis, Nagasaki 8528523, Japan
关键词
TRANSCRIPTION FACTOR NRF2; INCLUSION-BODY FORMATION; P62; PROTEASOME; AUTOPHAGY; UBIQUITIN; PRP; DEGRADATION; INHIBITION; STRESS;
D O I
10.1038/srep04504
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Prion diseases are neurodegenerative disorders characterized by the aggregation of abnormally folded prion protein (PrPSc). In this study, we focused on the mechanism of clearance of PrPSc, which remains unclear. p62 is a cytosolic protein known to mediate both the formation and degradation of aggregates of abnormal proteins. The levels of p62 protein increased in prion-infected brains and persistently infected cell cultures. Upon proteasome inhibition, p62 co-localized with PrPSc, forming a large aggregate in the perinuclear region, hereafter referred to as PrPSc-aggresome. These aggregates were surrounded with autophagosome marker LC3 and lysosomes in prion-infected cells. Moreover, transient expression of the phosphomimic form of p62, which has enhanced ubiquitin-binding activity, reduced the amount of PrPSc in prion-infected cells, indicating that the activation of p62 could accelerate the clearance of PrPSc. Our findings would thus suggest that p62 could be a target for the therapeutic control of prion diseases.
引用
收藏
页数:7
相关论文
共 49 条
[1]   Autophagy induction by trehalose counteracts cellular prion infection [J].
Aguib, Yasmine ;
Heiseke, Andreas ;
Gilch, Sabine ;
Riemer, Constanze ;
Baier, Michael ;
Schaetzl, Hermann M. ;
Ertmer, Alexa .
AUTOPHAGY, 2009, 5 (03) :361-369
[2]   Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].
Arrasate, M ;
Mitra, S ;
Schweitzer, ES ;
Segal, MR ;
Finkbeiner, S .
NATURE, 2004, 431 (7010) :805-810
[3]   Prion strain-dependent differences in conversion of mutant prion proteins in cell culture [J].
Atarashi, Ryuichiro ;
Sim, Valerie L. ;
Nishida, Noriyuki ;
Caughey, Byron ;
Katamine, Shigeru .
JOURNAL OF VIROLOGY, 2006, 80 (16) :7854-7862
[4]   Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation [J].
Babu, JR ;
Geetha, T ;
Wooten, MW .
JOURNAL OF NEUROCHEMISTRY, 2005, 94 (01) :192-203
[5]   Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation [J].
Bennett, EJ ;
Bence, NF ;
Jayakumar, R ;
Kopito, RR .
MOLECULAR CELL, 2005, 17 (03) :351-365
[6]   p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death [J].
Bjorkoy, G ;
Lamark, T ;
Brech, A ;
Outzen, H ;
Perander, M ;
Overvatn, A ;
Stenmark, H ;
Johansen, T .
JOURNAL OF CELL BIOLOGY, 2005, 171 (04) :603-614
[7]   CREUTZFELDT-JAKOB DISEASE PRION PROTEINS IN HUMAN BRAINS [J].
BOCKMAN, JM ;
KINGSBURY, DT ;
MCKINLEY, MP ;
BENDHEIM, PE ;
PRUSINER, SB .
NEW ENGLAND JOURNAL OF MEDICINE, 1985, 312 (02) :73-78
[8]   Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry [J].
Deriziotis, Pelagia ;
Andre, Ralph ;
Smith, David M. ;
Goold, Rob ;
Kinghorn, Kerri J. ;
Kristiansen, Mark ;
Nathan, James A. ;
Rosenzweig, Rina ;
Krutauz, Dasha ;
Glickman, Michael H. ;
Collinge, John ;
Goldberg, Alfred L. ;
Tabrizi, Sarah J. .
EMBO JOURNAL, 2011, 30 (15) :3065-3077
[9]   p62/SQSTM1 Differentially Removes the Toxic Mutant Androgen Receptor via Autophagy and Inclusion Formation in a Spinal and Bulbar Muscular Atrophy Mouse Model [J].
Doi, Hideki ;
Adachi, Hiroaki ;
Katsuno, Masahisa ;
Minamiyama, Makoto ;
Matsumoto, Shinjiro ;
Kondo, Naohide ;
Miyazaki, Yu ;
Iida, Madoka ;
Tohnai, Genki ;
Qiang, Qiang ;
Tanaka, Fumiaki ;
Yanagawa, Toru ;
Warabi, Eiji ;
Ishii, Tetsuro ;
Sobue, Gen .
JOURNAL OF NEUROSCIENCE, 2013, 33 (18) :7710-7727
[10]   Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation [J].
Drisaldi, B ;
Stewart, RS ;
Adles, C ;
Stewart, LR ;
Quaglio, E ;
Biasini, E ;
Fioriti, L ;
Chiesa, R ;
Harris, DA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (24) :21732-21743