title: Differential distribution of the normal and mutated forms of huntingtin in the human brain.
abstract: Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease, supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: G
authors.initials: G
authors.lastname: Cancel
authors.forename: Y
authors.initials: Y
authors.lastname: Trottier
authors.forename: D
authors.initials: D
authors.lastname: Devys
authors.forename: L
authors.initials: L
authors.lastname: Tora
authors.forename: Y
authors.initials: Y
authors.lastname: Lutz
authors.forename: G
authors.initials: G
authors.lastname: Imbert
authors.forename: F
authors.initials: F
authors.lastname: Saudou
authors.forename: G
authors.initials: G
authors.lastname: Stevanin
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.forename: J L
authors.initials: JL
authors.lastname: Mandel
authors.forename: E C
authors.initials: EC
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001923:Brain Chemistry; D016923:Cell Death / Q000235:genetics; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins / Q000032:analysis* / Q000235:genetics* / Q000276:immunology; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins