In Huntington’s Disease (HD), aberrant splicing of the huntingtin protein can produce a highly toxic peptide that accumulates in the brain. The invention describes methods to minimize the toxicity of spliced proteins.
Huntington’s Disease (HD) is caused by an expanded polyglutamine region in the N-terminal fragment of the huntingtin protein (HTT) that can result from aberrant protein splicing. These N-terminal fragments are prevalent in post mortem HD tissue and expression of some of these fragments is sufficient to cause pathology in HD animal model. Thus, targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets for HD pathogenesis.
When the first intron of HTT is not spliced out, the protein fragment HTT exon 1 remains. The resulting HTT protein is high toxic. Interestingly, the addition of amino acids to the peptide sequence, however, renders the molecule much less toxic. Other small changes in the C-terminus of other HTT peptides also have profound effects on pathology. No investigation currently focuses on the extreme pathogenicity of the exon 1 fragment. UCI researchers seek to add amino acids to the C-terminus of HTT peptides to alter pathogenicity.
The invention of a novel method to reduce the levels of toxic HTT exon 1 fragments provides a promising approach to target peptide fragments likely to have the greatest impact on HD pathology.
Therapeutic target for HD
§ Concept only
§ Investigated the relative toxicities of different naturally occurring HTT fragments in a Drosophila model under controlled genetic background, transgene expression levels and post-translational proteolytic processing
§ Demonstrated HTT exon 1 peptide is exceptionally pathogenic
§ Planned experiments include comparing toxicity and pathology of read through vs. control proteins in vivo and testing read-through drug rescue