Student Olathe North High School Olathe, Kansas, United States
Kaitlyn Savoy (Olathe North High School)| Alex Cummins (Olathe North High School)| Grant Henrichs (Olathe North High School)
The PSEN1 gene located on chromosome 14 encodes the presenilin-1 (PS1) protein, the catalytic subunit of the 𝛾-secretase complex responsible for cleaving type 1 transmembrane proteins including amyloid-beta precursor protein (APP), which plays a role in Alzheimer’s disease (AD).The Olathe North MSOE Center for BioMolecular Modeling MAPS team examined various pathogenic mutations of the PSEN1 gene to identify relationships between mutated PS1 structure and function and AD. PS1 consists of 9 transmembrane (TM) domains. During maturation of the 𝛾-secretase complex, the protein is cleaved at an endoproteolytic site within the large hydrophilic loop between TM6 and TM7, yielding a 30 kDa N-terminal fragment (NTF) and 20 kDa C-terminal fragment (CTF). A catalytic aspartate residue in TM6 (asp257) and TM7 (asp385) are key for 𝛾-secretase substrate-cleavage activity. Mutation of the large hydrophilic loop, the endoproteolytic site, or either catalytic aspartate interferes with APP binding, decreasing beta-amyloid (Aβ) production. Of the more than 200 known pathogenic PSEN1 mutations, all result in an increased ratio of Aβ42 to Aβ40 and aggregation of Aβ42. They do not interfere with stable PS1 expression or 𝛾-secretase assembly and thus are thought to primarily affect catalytic 𝛾-secretase activity by reducing the stability of the protein-substrate complex, leading to premature release of Aβ42. The large majority of pathogenic PSEN1 mutations interfere with 𝛾-secretase subunit or APP interaction, resulting in somewhat, greatly, or completely diminished Aβ production, typically with greater effect on Aβ40 than Aβ42. Current studies regarding AD-causing PSEN1 mutations involve observation of the severity of the impact of mutations on Aβ production and examination of mechanisms of pathogenesis. Phosphorylation of several allosteric sites on PS1 has recently been found to be responsible for the pathogenic ‘closed’ conformation of PS1, resulting in βCTF degradation and decreased Aβ production. It has been consequently hypothesized that phosphorylation of these sites may be effective in reducing or preventing plaque formation as a therapy or prevention for AD, providing avenues for further research.