Critical role of the proline-rich region in Huntingtin for aggregation and cytotoxicity in yeast

被引:103
作者
Dehay, Benjamin [1 ]
Bertolotti, Anne [1 ]
机构
[1] Ecole Normale Super, CNRS, UMR 8541, Genet Mol Lab, F-75230 Paris 05, France
关键词
D O I
10.1074/jbc.M605558200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nine neurodegenerative diseases, such as Huntington, are caused by a polyglutamine ( poly( Q)) expansion in otherwise unrelated proteins. Although poly( Q) expansion causes aggregation of the affected proteins, the protein context might determine the selective neuronal vulnerability found in each disease. Here we have report that, although expression of Huntingtin derivatives with a pathological poly( Q) expansion are innocuous in yeast, deletion of the flanking proline-rich region alters the shape and number of poly( Q) inclusions and unmasks toxic properties. Strikingly, deletion of Hsp104 increases the size of inclusions formed by expanded poly( Q) lacking the proline-rich region and abolishes toxicity. Overexpression of the chaperones Hsp104 or Hsp70 rescues growth defects in affected cells without resolving inclusions. However, aggregates formed by nontoxic Huntingtin derivatives or by toxic derivatives cured by chaperones are physically distinct from aggregates formed by toxic proteins. This study identifies the proline-rich region in Huntingtin as a profound cis-acting modulator of expanded poly( Q) toxicity and distinguishes between aggregates of toxic or non-toxic proteins.
引用
收藏
页码:35608 / 35615
页数:8
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[41]   THE DELETION OF THE PROLINE-RICH REGION OF HOXB4 LEADS TO MYELOID LEUKEMIA IN MICE [J].
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Rawat, V. P. S. ;
Hiddemann, W. ;
Quintanilla-Martinez, L. ;
Humphries, R. K. ;
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Buske, C. .
ANNALS OF HEMATOLOGY, 2011, 90 :S14-S14
[42]   Affinity adsorbents for proline-rich peptide sequences: a new role for WW domains [J].
Dias, A. M. G. C. ;
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Iranzo, O. ;
Roque, A. C. A. .
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[43]   Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain ( vol 147 , pg 2098 , 2024) [J].
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Mesnard-Hoaglin, Nichole A. ;
Mays, Sarah ;
Priego, Mercedes ;
Dziechciowska, Joanna ;
Morris, Sarah ;
Kang, Minsu ;
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Klein, Alison ;
Gaona, Angelica ;
Melloni, Alexandra ;
Connors, Theresa ;
Hyman, Bradley ;
Song, Yuyu ;
Morfini, Gerardo A. .
BRAIN, 2025,
[44]   Association of elongation factor 1 alpha and ribosomal protein 13 with the proline-rich region of yeast adenylyl cyclase-associated protein CAP [J].
Yanagihara, C ;
Shinkai, M ;
Kariya, K ;
YamawakiKataoka, Y ;
Hu, CD ;
Masuda, T ;
Kataoka, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 232 (02) :503-507
[45]   The role of the proline-rich region in A1-type myosin essential light chains: Implications for information transmission in the actomyosin complex [J].
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Trayer, IP .
FEBS LETTERS, 1997, 400 (01) :31-36
[46]   Proline-Rich Region II (PRR2) Plays an Important Role in Tau-Glycan Interaction: An NMR Study [J].
Murray, Anqesha ;
Yan, Lufeng ;
Gibson, James M. ;
Liu, Jian ;
Eliezer, David ;
Lippens, Guy ;
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Linhardt, Robert J. ;
Zhao, Jing ;
Wang, Chunyu .
BIOMOLECULES, 2022, 12 (11)
[47]   Development of cross-reactive antibodies to the proline-rich region of pneumococcal surface protein A in children [J].
Melin, Merit ;
Coan, Pat ;
Hollingshead, Susan .
VACCINE, 2012, 30 (50) :7157-7160
[48]   A PROLINE-RICH PROTEIN, VERPROLIN, INVOLVED IN CYTOSKELETAL ORGANIZATION AND CELLULAR GROWTH IN THE YEAST SACCHAROMYCES-CEREVISIAE [J].
DONNELLY, SFH ;
POCKLINGTON, MJ ;
PALLOTTA, D ;
ORR, E .
MOLECULAR MICROBIOLOGY, 1993, 10 (03) :585-596
[49]   RHEOLOGICAL PROPERTIES OF HUMAN BRONCHIAL-SECRETIONS - DEMONSTRATION OF PROLINE-RICH POLYPEPTIDES AND THEIR ROLE [J].
BAILLEUL, V ;
RICHET, C ;
HAYEM, A ;
DEGAND, P .
CLINICA CHIMICA ACTA, 1977, 74 (02) :115-123
[50]   THE PROLINE-RICH REGION OF VAV BINDS TO GRB2, AND GRB3-3 [J].
RAMOSMORALES, F ;
ROMERO, F ;
SCHWEIGHOFFER, F ;
BISMUTH, G ;
CAMONIS, J ;
TORTOLERO, M ;
FISCHER, S .
ONCOGENE, 1995, 11 (08) :1665-1669