Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Specific combinations of presenilin 1 protein regions are required for differential cleavage of amyloid precursor protein and notch receptor (#123)

Melissa Eccles 1 , Shinsuke Matsuzaki 2 , Miheer Sabale 1 , David Groth 1 , Paul Fraser 2 , Giuseppe Verdile 1 3
  1. School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia
  2. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
  3. Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia

The homologous proteins presenilin-1 (PS1) and presenilin-2 (PS2) are the essential catalytic component of γ-secretase, which processes multiple substrates including Amyloid Precursor Protein (APP) and Notch receptor. APP cleavage produces amyloid-β (Aβ) peptides which accumulate early in Alzheimer’s disease, and Notch processing regulates critical cellular functions. PS1 and PS2 form discrete γ-secretase enzymes, and are the primary determinants of enzyme activity. PS1 complexes are significantly more active than PS2 complexes, both for APP and Notch processing. Sequence alignment of PS1 and PS2 identifies four regions of high sequence divergence; N-terminal tail (Nt), transmembrane (TM) domains 3 and 4 (TM3-4), cytoplasmic loop (CyLp), and C-terminal half of TM9 to C-terminus (Ct). The functional importance of these regions was investigated by assessing activity on APP and Notch of chimeric proteins, in which selected PS1 protein regions were inserted into PS2.  Results showed that PS1-TM3-4 combined with the PS1-Ct region, significantly increases PS2 activity to process APP and generate Aβ40 and Aβ42. However, only PS1-TM3-4 was required to increase PS2 activity to process Notch. This finding indicates that different PS1 regions are responsible for APP and Notch processing and represents the first important step in identifying new molecular targets that may enable specific modulation of APP processing to reduce Aβ production.