title: Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's disease.
abstract: Nearly 200 mutations in the gene coding for presenilin 1 (PSEN1) cause early-onset Alzheimer's disease, yet the molecular mechanism remains obscure. As a meta-analysis, we compiled available clinical and biochemical data for PSEN1 variants and correlated these to chemical properties of the mutants. We found statistically significant relationships between relative Aβ42 levels and clinical age of onset. We then computed chemical properties of the mutants from a variety of computational chemistry tools. Relative Aβ42 levels correlated significantly (95% confidence or more from p-values of linear regression) with loss of hydrophobicity for four different regression analyses (squared correlation coefficient of linear regression R(2) of 0.41-0.53) and with increased polarity (R(2) = 0.47, 0.59) and loss of protein stability (R(2) = 0.39, 0.63) for two independent data sets. Age of onset of patients carrying PSEN1 variants correlated with increased polarity (R(2) = 0.49, 0.40) and loss of stability (R(2) = 0.75, 0.44) of the protein for both data sets. These relations suggest that mutants impair the membrane-associated structural integrity of presenilin by reducing hydrophobic membrane association and overall protein stability. This explains why the many mutations that spread out across the protein and far from the catalytic aspartates can cause disease. The identified molecular determinants of clinical age of symptom onset may be relevant to future presenilin-modulating therapies specifically directed towards increasing the structural integrity and packing of the protein. Close to 200 mutations in presenilin 1 (PSEN1) cause Alzheimer's disease, but the biochemical relating these to disease remains debated. The chemical properties of PSEN1 variants were computed and correlated against clinical age of symptom onset. Loss of stability and hydrophobicity and gain of polarity relate to disease onset, suggesting that mutants impair the membrane structure of PSEN1 and that therapies should increase PSEN1 structural integrity.
authors.affiliation: Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Somavarapu
authors.affiliation: Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.
authors.forename: Kasper P
authors.identifier: http://orcid.org/0000-0002-6754-7348
authors.initials: KP
authors.lastname: Kepp
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000032:analysis; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D066264:Datasets as Topic; D005799:Genes, Dominant; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000032:analysis; D017354:Point Mutation; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D055550:Protein Stability; D012044:Regression Analysis
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's Disease; Presenilin; chemical properties; genotype-phenotype relation; mutation