Origins of amyloid-β

BMC Genomics

Research Article

Indra Neil Sarkar¹  William G Tharp² 

[1] Center for Clinical and Translational Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, 05405, Burlington, VT, USA;Department of Microbiology and Molecular Genetics, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, 05405, Burlington, VT, USA;Department of Computer Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, 05405, Burlington, VT, USA;Center for Clinical and Translational Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, 05405, Burlington, VT, USA;Division of Endocrinology, Department of Medicine, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, 05405, Burlington, VT, USA;

关键词: Amyloid;    Alzheimer disease;    Phylogenetics;    In silico;    Aggregation;    Maximum parsimony;    Bayesian inference;   

DOI  :  10.1186/1471-2164-14-290

 received in 2012-11-16, accepted in 2013-04-24,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAmyloid-β plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-β deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-β deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment.ResultsIn this study, we asked when amyloidogenic Amyloid-β first arose using phylogenetic trees constructed for the Amyloid-β Precursor Protein gene family and by modeling the potential for Amyloid-β aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-β Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-β Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-β Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues.ConclusionsThe Amyloid-β Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-β domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyoid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-β formation as the peptide sequence.

【 授权许可】

CC BY   
© Tharp and Sarkar; licensee BioMed Central Ltd. 2013