Homopolymeric alanine repeats: structure, function, and mechanistic role in the pathogenesis of polyalanine expansion genetic diseases

A number of diseases - including Cleidocranial Dysplasia, Oculopharyngeal Muscular Dystrophy and Holoprosencephaly 5 - derive from the same type of genetic mutation that causes the expansion of certain repetitive tracts of DNA. These DNA tracts normally encode for short repeats of the amino acid alanine in proteins, called polyalanine (polyA) repeats. When polyA repeats become too long - as a consequence of mutation - they cause disease by inducing protein dysfunction, aggregation, and, ultimately, cellular damage. The search for effective therapies of these diseases requires a clear understanding of the mechanisms by which elongated polyA tracts cause protein and cell dysfunction. However, these mechanisms are still poorly understood, and little is known even about the physiological function of normal polyA repeats. Despite the absence of conclusive evidence, polyA expansion diseases are currently thought to derive from a change in the conformation ("misfolding") of expanded polyA repeats that would form pathogenic “β-sheet” structures leading to protein aggregation/dysfunction. Another group of genetic diseases such as Huntington's disease, is similarly caused by the expansion of repeats encoding for glutamine. We have recently discovered that polyglutamine (polyQ) expansion may cause protein dysfunction and aggregation primarily through the formation of "α-helical coiled-coil" structures, rather than through β-sheet misfolding. Preliminary studies carried out in our laboratory indicate the possibility that coiled coils may also mediate the physiological and pathological actions of polyA repeats. This research project specifically aims at testing the hypothesis that polyA and polyQ diseases may share a common pathogenetic mechanism based on the formation of coiled coils triggering protein aggregation/toxicity. By defining the precise molecular mechanism of polyA expansion diseases, our studies may help us to identify novel therapies for these severe disorders.