title: Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease.
abstract: Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. However, many factors can contribute to pathology, including genetic background and differential expression of transgenes, in addition to intrinsic differences between fragments and their cellular effects. We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. These studies reveal that among the naturally occurring N-terminal HTT peptides, the exon 1 peptide is exceptionally pathogenic and exhibits unique structural and biophysical behaviors that do not appear to be incremental changes compared with other fragments. If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post-translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Barbaro
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Lukacsovich
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA, Department of Zoology, University of Delhi, Delhi 110007, India.
authors.forename: Namita
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: John
authors.initials: J
authors.lastname: Burke
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bornemann
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Purcell
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Worthge
authors.affiliation: Promidis, Rome, Italy and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.affiliation: Promidis, Rome, Italy and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Morozova
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Colby
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine 92697, USA, jlmarsh@uci.edu.
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins; D005091:Exons; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis
chemical_list: D000682:Amyloid; D029721:Drosophila Proteins; C086055:HTT protein, human; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine