Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein.
Huntington's Disease (HD) is a dominantly inherited pathology caused by the accumulation of mutant huntingtin protein (HTT) containing an expanded polyglutamine (polyQ) tract. As the polyglutamine binding peptide 1 (QBP1) is known to bind an expanded polyQ tract but not the polyQ motif found in normal HTT, we selectively targeted mutant HTT for degradation by expressing a fusion molecule comprising two copies of QBP1 and copies of two different heat shock cognate protein 70 (HSC70)-binding motifs in cellular and mouse models of HD. Chaperone-mediated autophagy contributed to the specific degradation of mutant HTT in cultured cells expressing the construct. Intrastriatal delivery of a virus expressing the fusion molecule ameliorated the disease phenotype in the R6/2 mouse model of HD. Similar adaptor molecules comprising HSC70-binding motifs fused to an appropriate structure-specific binding agent(s) may have therapeutic potential for treating diseases caused by misfolded proteins other than those with expanded polyQ tracts.
Bauer
Peter O
PO
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Goswami
Anand
A
Wong
Hon Kit
HK
Okuno
Misako
M
Kurosawa
Masaru
M
Yamada
Mizuki
M
Miyazaki
Haruko
H
Matsumoto
Gen
G
Kino
Yoshihiro
Y
Nagai
Yoshitaka
Y
Nukina
Nobuyuki
N
D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*
D050883:HSC70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; C407346:polyglutamine-binding protein 1; C097188:polyglutamine