title: Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease.
abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of glutamine repeats in the huntingtin (htt) protein. Abnormal protein folding and the accumulation of mutated htt are hallmarks of HD neuropathology. Heat-shock proteins (hsps), which refold denatured proteins, might therefore mitigate HD. We show here that hsp104 and hsp27 rescue striatal dysfunction in primary neuronal cultures and HD rat models based on lentiviral-mediated overexpression of a mutated htt fragment. In primary rat striatal cultures, production of hsp104 or hsp27 with htt171-82Q restored neuronal nuclei (NeuN)-positive cell density to that measured after infection with vector expressing the wild-type htt fragment (htt171-19Q). In vivo, both chaperones significantly reduced mutated-htt-related loss of DARPP-32 expression. Furthermore, hsps affected the distribution and size of htt inclusions, with the density of neuritic aggregates being remarkably increased in striatal neurons overexpressing hsps. We also found that htt171-82Q induced the up-regulation of endogenous hsp70 that was co-localized with htt inclusions, and that the overexpression of hsp104 and hsp27 modified the subcellular localization of hsp70 that became cytoplasmic. Finally, hsp104 induced the production of endogenous hsp27. These data demonstrate the protective effects of chaperones in mammalian models of HD.
authors: Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne, Switzerland.
authors: Valérie
authors: V
authors: Perrin
authors: Etienne
authors: E
authors: Régulier
authors: Toufik
authors: T
authors: Abbas-Terki
authors: Raymonde
authors: R
authors: Hassig
authors: Emmanuel
authors: E
authors: Brouillet
authors: Patrick
authors: P
authors: Aebischer
authors: Ruth
authors: R
authors: Luthi-Carter
authors: Nicole
authors: N
authors: Déglon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics*; D018613:Microscopy, Confocal; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017072:Neostriatum / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae