title: Cholinergic neuronal defect without cell loss in Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.
authors.affiliation: Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden.
authors.forename: Ruben
authors.initials: R
authors.lastname: Smith
authors.forename: Hinfan
authors.initials: H
authors.lastname: Chung
authors.forename: Sara
authors.initials: S
authors.lastname: Rundquist
authors.forename: Marion L C
authors.initials: ML
authors.lastname: Maat-Schieman
authors.forename: Lesley
authors.initials: L
authors.lastname: Colgan
authors.forename: Elisabet
authors.initials: E
authors.lastname: Englund
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Liu
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D001923:Brain Chemistry; D016022:Case-Control Studies; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D018782:Maze Learning; D026901:Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000378:metabolism; D009133:Muscular Atrophy; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002795:Choline O-Acetyltransferase; D000071058:Huntingtin Protein; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010830:Physostigmine; D012097:Repressor Proteins; D014157:Transcription Factors; D050494:Vesicular Acetylcholine Transport Proteins; D000099229:RE1-Silencing Transcription Factor; C506812:Htt protein, mouse; C065637:choline transporter