title: Expanded polyglutamine-containing N-terminal huntingtin fragments are entirely degraded by mammalian proteasomes.
abstract: Huntington disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat within the protein huntingtin (Htt). N-terminal fragments of the mutant Htt (mHtt) proteins containing the polyQ repeat are aggregation-prone and form intracellular inclusion bodies. Improving the clearance of mHtt fragments by intracellular degradation pathways is relevant to obviate toxic mHtt species and subsequent neurodegeneration. Because the proteasomal degradation pathway has been the subject of controversy regarding the processing of expanded polyQ repeats, we examined whether the proteasome can efficiently degrade Htt-exon1 with an expanded polyQ stretch both in neuronal cells and in vitro. Upon targeting mHtt-exon1 to the proteasome, rapid and complete clearance of mHtt-exon1 was observed. Proteasomal degradation of mHtt-exon1 was devoid of polyQ peptides as partial cleavage products by incomplete proteolysis, indicating that mammalian proteasomes are capable of efficiently degrading expanded polyQ sequences without an inhibitory effect on the proteasomal activity.
authors.affiliation: Department of Cellbiology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Electronic address: k.junemann@amc.uva.nl.
authors.forename: Katrin
authors.initials: K
authors.lastname: Juenemann
authors.affiliation: Department of Cellbiology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schipper-Krom
authors.affiliation: Department of Cellbiology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Wiemhoefer
authors.affiliation: Institut für Biochemie/CCM, Charité-Universitätsmedizin Berlin, Monbijoustrasse 2, Berlin 10117, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kloss
authors.affiliation: Department of Cellbiology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sanz Sanz
authors.affiliation: Department of Cellbiology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Electronic address: e.a.reits@amc.uva.nl.
authors.forename: Eric A J
authors.initials: EAJ
authors.lastname: Reits
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D020449:Repetitive Sequences, Amino Acid
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex
keywords: Aggregation; Autophagy; Huntington Disease; Polyglutamine; Proteasome
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