“A molecular mechanism for Alzheimer’s disease: the effects of WT and mutant Presenilin D257A on TrpC5 channel function.” Blog #1

My name is Paris Hanson, I am a rising junior at Pace, a biology major, and this summer I am so excited to be working with Dr. Zafir Buraei on our research “A molecular mechanism for Alzheimer’s disease: the effects of WT and mutant Presenilin D257A on TrpC5 channel function.”
Mutations found in Presenilin genes (PSEN1 & PSEN2) can be accounted for majority of the early onset FAD mutations. Presenilin FAD mutations have been shown to alter calcium signaling. Recently, studies show that Presenilin itself can be a ‘leak’ channel on the ER that depletes Ca2+ ions from the smooth ER. This discovery led us to investigate the possible crosstalk between Presenilin and intracellular calcium signaling, as it relates to TrpC5 chanel activation. TrpC5 is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel.
Previous research conducted by resent graduate Sukhjinder Kaur and Dr. Buraei investigated the effects of Presenilin on TrpC5 Channel function. A result of the experiment found that that co-expression of WT Presenilin resulted in a significant decrease in agonist evoked TrpC5 channel currents. A plausible explanation is that Presenilin expression renders the ER somewhat Ca2+-poor, and subsequent Ca2+ efflux through IP3 receptors -required for TrpC5 activation is significantly diminished. They also tested the effect of FAD mutant Presenilin M146V on TrpC5 channel activity, finding that that Pres-WT decreases TRPC5 currents, whereas, Pres-M146V does not inhibit TrpC5 as effectively. This may have a significant impact in the pathogenesis of Alzheimer’s disease, especially when Presenilin1 is mutated. Presenilin FAD mutation D257A, a mutation that is known to abolish γ-secretase activity, does not seem to impact the function of presenilin as an ER leak channel.
Thus, our purpose is to determine how different presenilin mutants effect TrpC5 activity. We predict that, similarly to presenilin, presenilin FAD mutation D257A would act like the WT channel and decrease TrpC5 channel activation. Another mutation found in Presenilin D385A was shown to completely abolish calcium leak channel activity on the ER. Testing D385A co-expressed with TRPC5 in oocytes may reveal an effect similar to (xyz, the mutation we detest) and shine a new light on the etiology of Alzheimer’s disease.
Overall, our goal is to use mutant Pres-M146V and wild-type presenilin to confirm the previous studies as well as to synthesize Presenilin FAD mutation D257A in order to perform electrophysiological studies and analyze our results.

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