Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions.
Proteolytic processing of mutant huntingtin (mhtt) is regarded as a key event in the pathogenesis of Huntington's disease (HD). Mhtt fragments containing a polyglutamine expansion form intracellular inclusions and are more cytotoxic than full-length mhtt. Here, we report that two distinct mhtt fragments, termed cp-A and cp-B, differentially build up nuclear and cytoplasmic inclusions in HD brain and in a cellular model for HD. Cp-A is released by cleavage of htt in a 10 amino acid domain and is the major fragment that aggregates in the nucleus. Furthermore, we provide evidence that cp-A and cp-B are most likely generated by aspartic endopeptidases acting in concert with the proteasome to ensure the normal turnover of htt. These proteolytic processes are thus potential targets for therapeutic intervention in HD.
Lunkes
Astrid
A
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P.163, 67404 Illkirch Cédex, CU de Strasbourg, France. astrid.lunkes@embo.org
Lindenberg
Katrin S
KS
Ben-Haïem
Léa
L
Weber
Chantal
C
Devys
Didier
D
Landwehrmeyer
G Bernhard
GB
Mandel
Jean-Louis
JL
Trottier
Yvon
Y
D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010450:Endopeptidases