Referent: Prof. Andreas Neueder (Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf)
Titel: RNA Biology and HTT Fragment Generation by Incomplete Splicing in Huntington Disease
Abstract: Expansions of microsatellites, repetitive nucleotide sequences scattered throughout the genome, are the cause of a number of diseases. Huntington disease (HD) is the most common disease of a family of disorders that is caused by expansions of a CAG triplet sequence in their coding region. Huntingtin (HTT), the gene harbouring the expanded CAG repeat in HD, is a ubiquitously expressed, and alternatively spliced gene that gives rise to several canonical and numerous disease related isoforms. Alternative splicing of the HTT gene and proteolytic cleavage of the HTT protein generate C-terminally truncated fragments of HTT. The severity of disease and molecular phenotypes is strongly correlated with smaller N-terminal fragments. The most toxic fragment of HTT is encoded by exon 1, which includes the expanded CAG tract, and induces both protein and RNA based toxicity. We have shown that this fragment is translated from a novel, disease-related isoform of HTT, HTT1a, that is generated by a block in the splicing of exon 1 to exon 2.
