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 Ab 42 levels and clinical age of onset. We then computed chemical properties of the mutants from a variety of computational chemistry tools. Relative Ab 42 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 0.41À0.53) 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 presenilinmodulating therapies specifically directed towards increasing the structural integrity and packing of the protein.

Molecular dynamics of C99-bound γ-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: implications for Aβ production

“…These findings are in accordance with the FIST model (Fit-Stay-Trim) of C99 processing [42,43]. They are also supported by the observation that Aβ 42 /Aβ 40 ratios of FAD-causing PSEN1 mutations correlate with disease severity [44], and both of these correlate with the tendency of the mutation to chemically stabilize the hydrophobic packing of the protein complex within the membrane, with PSEN1 mutations generally loosing thermochemical stability and/or hydrophobicity [83].…”

Alzheimer’s disease: How metal ions define β-amyloid function

“…Combined with the fact that many AD-causing mutations display reduced Aβ levels [165], and the many reports that physiological concentrations of Aβ1−40 are beneficial to the were ever considered meaningful strategies. Yet proponents of the amyloid-alone scenario suggest that the failure of γ-secretase inhibitors is due to adverse effects of reducing other γ-secretase functions, and the failure of antibodies is excused by not having targeted the right Aβ forms [12,122].…”

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

“…how does this produce gradual buildup of toxic oligomers emphasized by the amyloid hypothesis [133]. This ratio has recently been directly correlated to clinical severity, although this does not necessarily imply causation [97]. It could be that reduced enzymatic function causes disease and that higher ratios is a side consequence [132] [134].…”

“…Many of the characterized FAD-causing mutations in PSEN1 impair γ-secretase function while increasing the A42/A40 ratio [69] [96]; some do so while increasing, others while decreasing total A levels which are dominated by the A40 isoform [97] [98]. Indeed, increased proficiency of so many mutations would be a priori unlikely, as proteins are optimized by evolution to perform optimally under the constraints given, and thus most mutations tend to be hypomorphic [99].…”