Abstract
BackgroundHuntington's disease is an inherited neurodegenerative disorder that is caused by the expansion of an N-terminal polyQ stretch in the huntingtin protein. In order to investigate the hypothesis that huntingtin was already involved in development of the nervous system in the last common ancestor of chordates, we isolated and characterised the huntingtin homologue from the amphioxus Branchiostoma floridae. In the present paper the amphioxus general term must be referred to Branchiostoma floridae.ResultsIn this report, we show that the exon-intron organization of the amphioxus huntingtin gene is highly conserved with that of other vertebrates species. The AmphiHtt protein has two glutamine residues in the position of the typical vertebrate polyQ tract. Sequence conservation is greater along the entire length of the protein than in a previously identified Ciona huntingtin. The first three N-terminal HEAT repeats are highly conserved in vertebrates and amphioxus, although exon rearrangement has occurred in this region. AmphiHtt expression is detectable by in situ hybridization starting from the early neurula stage, where it is found in cells of the neural plate. At later stages, it is retained in the neural compartment but also it appears in limited and well-defined groups of non-neural cells. At subsequent larval stages, AmphiHtt expression is detected in the neural tube, with the strongest signal being present in the most anterior part.ConclusionThe cloning of amphioxus huntingtin allows to infer that the polyQ in huntingtin was already present 540 million years ago and provides a further element for the study of huntingtin function and its evolution along the deuterostome branch.
Highlights
Huntington's disease is an inherited neurodegenerative disorder that is caused by the expansion of an N-terminal polyQ stretch in the huntingtin protein
We describe for the first time the distribution of huntingtin mRNA in this invertebrate chordate, whose nervous system development is close to that of vertebrates as it includes vertebrate-like anatomical characteristics such as a dorsal nerve cord, a notochord and segmentally arranged muscles
Cloning and characterisation of the amphioxus huntingtin sequence (AmphiHtt) Starting from the recently available B. floridae genomic sequencing data, two scaffolds were identified by means of TblastN similarity as possibly containing the huntingtin gene
Summary
Huntington's disease is an inherited neurodegenerative disorder that is caused by the expansion of an N-terminal polyQ stretch in the huntingtin protein. In the present paper the amphioxus general term must be referred to Branchiostoma floridae. Huntingtin is a completely soluble, ubiquitously expressed 350-kDa protein of 3144 aa which, once mutated, causes Huntington's disease (HD), a late-onset neurodegenerative disease characterised by movement disorders, dementia and psychiatric disturbances, and by preferential vulnerability of striatal and cortical neurons [1]. Recent studies have suggested that the polyP tract helps to maintain protein solubility [4]. It is possible that, during evolution, an expanded polyQ has conferred important molecular function(s) partially because of its cooperation with the emerging polyP tract. An aberrantly expanded polyQ region in huntingtin is sufficient to cause HD
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