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.