Aggregate formation and synaptic abnormality induced by DSCR1.
Aggregation of conformation-abnormal peptides probably plays a key role in the pathogenesis of many neurodegenerative diseases. DSCR1 Down syndrome (DS) critical region 1, was identified from a chromosomal region (21q22.1-q22.2) for the clinical manifestations of DS when an extra-copy is present. We report that expression of DSCR1 in several cell types, including primary neurons, causes microtubule-dependent aggresome-like inclusion body formation. Disease-associated huntingtin (Q148) and ataxin-3 (Q84) co-localize with DSCR1 aggregates. Neurons bearing DSCR1 aggregates show reduced synaptophysin staining in processes. DSCR1 residues 31-90 constitute an aggregation-prone domain that is predicted to form a hydrophobic patch on the protein surface when residues 1-30 are removed. This study identifies a novel function of DSCR1 that may underlie DS neuropathology.
Ma
Hong
H
The Burnham Institute, La Jolla, California 92037, USA.
Xiong
Hui
H
Liu
Tong
T
Zhang
Lingyan
L
Godzik
Adam
A
Zhang
Zhuohua
Z
D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D000067699:Ataxin-3; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000235:genetics; D046911:Macromolecular Substances; D008958:Models, Molecular; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D012097:Repressor Proteins; D013569:Synapses / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D046911:Macromolecular Substances; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C108612:RCAN1 protein, human; D012097:Repressor Proteins; D016708:Synaptophysin; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat