title: Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein.
abstract: Aggregation of disease proteins is believed to be a central event in the pathology of polyglutamine diseases, whereas the relationship between aggregation and neuronal death remains controversial. We investigated this question by expressing mutant huntingtin (htt) with a defective adenovirus in different types of neurons prepared from rat cerebral cortex, striatum or cerebellum. The distribution pattern of inclusions is not identical among different types of primary neurons. On day 2 after infection, cytoplasmic inclusions are dominant in cortical and striatal neurons, whereas at day 4 the ratio of nuclear inclusions overtakes that of cytoplasmic inclusions. Meanwhile, nuclear inclusions are always predominantly present in cerebellar neurons. The percentage of inclusion-positive cells is highest in cerebellar neurons, whereas mutant htt induces cell death most remarkably in cortical neurons. As our system uses htt exon 1 protein and thus aggregation occurs independently from cleavage of the full-length htt, our observations indicate that the aggregation process is distinct among different neurons. Most of the neurons containing intracellular (either nuclear or cytoplasmic) aggregates are viable. Our findings suggest that the process of mutant htt aggregation rather than the resulting inclusion body is critical for neuronal cell death.
authors.affiliation: Department of Molecular Therapeutics, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Hoshino
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okuda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ueda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Sabine
authors.initials: S
authors.lastname: Engemann
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
authors.forename: Masumi
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000196:embryology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D003593:Cytoplasm / Q000378:metabolism; D005091:Exons / Q000235:genetics; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017072:Neostriatum / Q000166:cytology / Q000196:embryology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments