Presenilin

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge. Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca²⁺ involved in presynaptic neurotransmitter release and long-term potentiation induction.

PSEN2

Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.

Function

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Two alternative transcripts of PSEN2 have been identified.

In melanocytic cells PSEN2 gene expression may be regulated by MITF.

Interactions

PSEN2 has been shown to interact with:

References

PSEN1

Presenilin-1 (PS-1) is a protein that in humans is encoded by the PSEN1 gene. Presenilin 1 is one of the four core proteins in presenilin complex, which mediate the regulated proteolytic events of several proteins in the cell, including gamma secretase. Gamma-secretase is considered to play a very important role in generation of beta amyloid, accumulation of which is related to the onset of Alzheimer's Disease, from the beta-amyloid precursor protein.

Structure

Presenilin possesses a 9 transmembrane topology, with an extracellular C-terminus and a cytosolic N-terminus. Presenilin is subject to undergo endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans. Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments. When presenilin 1 is over expressed, the full length protein accumulates in an inactive form. Based on evidence that a gamma-secretase inhibitor binds to the fragments, the cleaved presenilin complex is considered to be the active form.