Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease

• DOI: 10.1073/pnas.1221891110
• Publication Date: 2013-01-23T07:27:25Z
• Authors: Kirupa Sathasivam; Andreas Neueder; Theresa A. Gipson; Christian Landles; Agnesska C. Benjamin; Marie K. Bondulich; Donna L. Smith; Richard L. M. Faull; Raymund A. C. Roos; David Howland; Peter J. Detloff; David E. Housman; Gillian P. Bates
• Keywords: Polyglutamine tract; Huntingtin Protein

Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It caused by CAG repeat expansion in exon 1 of the HTT gene translates to polyglutamine tract huntingtin protein (HTT). The formation fragments has been implicated as an essential step molecular pathogenesis HD several proteases cleave have identified. However, importance smaller N-terminal highlighted their presence postmortem brains fact nuclear inclusions are only detected antibodies N terminus HTT. Despite intense research effort, precise length these mechanism which they generated remains unknown. Here we show length–dependent aberrant splicing results short polyadenylated mRNA translated into protein. Given mutant proteins consistently shown be highly pathogenic mouse models, provides mechanistic basis for HD. RNA-targeted therapeutic strategies designed lower levels under development. Many approaches would not prevent production should reviewed light our findings.