Shock and awe: unleashing the heat shock response to treat Huntington disease

被引:8
作者
Jackrel, Meredith E. [1 ]
Shorter, James [1 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA
关键词
PARKINSON-DISEASE; IN-VITRO; MODEL; PROTEOSTASIS; AGGREGATION; DROSOPHILA; DISTINCT; STRESS; VIVO;
D O I
10.1172/JCI59190
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The heat shock response (HSR) is a highly conserved protective mechanism that enables cells to withstand diverse environmental stressors that disrupt protein homeostasis (proteostasis) and promote protein misfolding. It has been suggested that small-molecule drugs that elicit the HSR by activating the transcription factor heat shock factor 1 might help mitigate protein misfolding and aggregation in several devastating neurodegenerative disorders, including Huntington disease (HD). In this issue of the JCI, Labbadia et al. use a brain-penetrant Hsp90 inhibitor, HSP990, to induce the HSR in mouse models of HD. Unexpectedly, they observed that HSP990 confers only transient amelioration of a subset of HD-related phenotypes, because alterations in chromatin architecture impair the HSR upon disease progression. These findings suggest that synergistic combination therapies that simultaneously unleash the HSR and prevent its impairment are likely to be needed to restore proteostasis in HD.
引用
收藏
页码:2972 / 2975
页数:4
相关论文
共 23 条
  • [1] Pharmacological prevention of Parkinson disease in Drosophila
    Auluck, PK
    Bonini, NM
    [J]. NATURE MEDICINE, 2002, 8 (11) : 1185 - 1186
  • [2] Adapting proteostasis for disease intervention
    Balch, William E.
    Morimoto, Richard I.
    Dillin, Andrew
    Kelly, Jeffery W.
    [J]. SCIENCE, 2008, 319 (5865) : 916 - 919
  • [3] Huntington's Disease: Can Mice Lead the Way to Treatment?
    Crook, Zachary R.
    Housman, David
    [J]. NEURON, 2011, 69 (03) : 423 - 435
  • [4] Prion-like disorders: blurring the divide between transmissibility and infectivity
    Cushman, Mimi
    Johnson, Brian S.
    King, Oliver D.
    Gitler, Aaron D.
    Shorter, James
    [J]. JOURNAL OF CELL SCIENCE, 2010, 123 (08) : 1191 - 1201
  • [5] Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity
    Duennwald, Martin L.
    Lindquist, Susan
    [J]. GENES & DEVELOPMENT, 2008, 22 (23) : 3308 - 3319
  • [6] Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models
    Fujimoto, M
    Takaki, E
    Hayashi, T
    Kitaura, Y
    Tanaka, Y
    Inouye, S
    Nakai, A
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (41) : 34908 - 34916
  • [7] Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach
    Hay, DG
    Sathasivam, K
    Tobaben, S
    Stahl, B
    Marber, M
    Mestril, R
    Mahal, A
    Smith, DL
    Woodman, B
    Bates, GP
    [J]. HUMAN MOLECULAR GENETICS, 2004, 13 (13) : 1389 - 1405
  • [8] Protein Homeostasis and the Phenotypic Manifestation of Genetic Diversity: Principles and Mechanisms
    Jarosz, Daniel F.
    Taipale, Mikko
    Lindquist, Susan
    [J]. ANNUAL REVIEW OF GENETICS, VOL 44, 2010, 44 : 189 - 216
  • [9] Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease
    Labbadia, John
    Cunliffe, Helen
    Weiss, Andreas
    Katsyuba, Elena
    Sathasivam, Kirupa
    Seredenina, Tamara
    Woodman, Ben
    Moussaoui, Saliha
    Frentzel, Stefan
    Luthi-Carter, Ruth
    Paganetti, Paolo
    Bates, Gillian P.
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (08) : 3306 - 3319
  • [10] HsP104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease
    Lo Bianco, Christophe
    Shorter, James
    Regulier, Etienne
    Lashuel, Hilal
    Iwatsubo, Takeshi
    Lindquist, Susan
    Aebischer, Patrick
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (09) : 3087 - 3097