Presenilin1 (PS1) is a transmembrane protein that is associated with secretase a
ID: 227395 • Letter: P
Question
Presenilin1 (PS1) is a transmembrane protein that is associated with secretase activity. Furthermore, it is implicated in the cleavage of amyloid precursor protein and the onset of Alzheimer's disease. In the brain, PS1 forms a complex with Ncadherin, a type I transmembrane protein. N-cadherin plays an important role in binding pre- and post-synaptic membranes together, i.e., between different neurons. To further understand the function of PS1 and the significance of its interaction with N-cadherin, knockout mice lacking both PS1 alleles were generated (Mara baud et al., 2003, Cell 114:635-645) Membrane preparations were obtained from neurons derived from PS1 knockout (PS1 -/-, lane 1) or wild-type (PS +/+, lane 2) mouse embryos and probed with an antibody that recognizes the cytoplasmic domain of N-cadherin, as shown below on the Western blot. N-Cad/FL is full length N-cadherin. N-Cad/CTF2 is a cytoplasmic terminal fragment of N-cadherin. Lanes 3 and 4 shows the results when membranes were prepared from neurons derived from a heterozygous (+/-) embryo and incubated for several hours in the absence (lane 3) or presence (lane 4) of a gamma secretase inhibitor. What function can you ascribe to PS1 based on these data? b) Jn. order to determine whether PS1 behavior is dependent on stimulation of neurons, wild-type mouse neurons were untreated (control) or were incubated in a high concentration of depolarizing the neurons and releasing neurotransmitter. Alternatively, the neurons were incubated in glutamate (L-g[y) or in NMDA, agonists that bind specifically to NMDA receptors and induce depolarization. This depolarization is inhibited by D-APV, an antagonist of the NMDA receptor. The data obtained are shown below in a Western blot generated using the same antibody as in part (a). What can you conclude from these data and that in part (a) about the signal transduction pathway leading to N-cadherin cleavage?Explanation / Answer
a)The function of PS1 protein must be a gain of function that leads the onset of Alzheimer disease.From the first western blot interpretation we can see there must be a missense mutation
b) we can decipher that here PS1 is responsible for signal transduction pathway leading to the cleavage of N-cadherin. CTF2 is formed by the cleavage of CTF1 by PS1, CTF2 may have some influence over gene transcription,which causes signal transduction pathway. By this pathway the malfunctioning of N-cadherin is initiated.