Deficient brain snRNP70K in patients with Down syndrome

The small nuclear ribonucleoprotein 70K (snRNP 70K; U1-70kDa) is an integra l part of the spliceosome, a large RNA-protein complex catalyzing the remov al of introns from nuclear pre-mRNA. snRNP is one of the best-studied essen tial subunits of snRNPs, is highly conserved and its inactivation was shown to result in complete inhibition of splicing. Applying subtractive hybridi zation, we found a sequence with 100% identity to snRNP absent in fetal Dow n syndrome (DS) brain. This observation made us determine snRNP-mRNA steady -state levels and protein levels in brains of adult patients with DS. snRNP -mRNA and protein levels of five individual brain regions of DS and control s each, were determined by blotting techniques, snRNP-mRNA steady state lev els were significantly decreased in DS brain. Performing Western blots with monoclonal and human antibodies, snRNP protein levels were decreased in se veral regions of DS brain, although one monoclonal antibody did not reveal different snRNP-immunoreactivity. Although decreased snRNP-protein could be explained by decreased mRNA-steady state levels, another underlying mechan ism might be suggested: snRNP is one of the death substrates rapidly cleave d during apoptosis by interleukin-1-beta-converting enzyme-like (ICE) prote ases, which was well-documented by several groups. As apoptosis is unrequiv ocally taking place in DS brain leading to permanent groups. Hs apoptosis I s unrequivocally taking place In vu brain leading to permanent cell loses, decreased snRNP-protein levels may therefore reflect decreased synthesis an d increased apoptosis-related proteolytic cleavage.