GSAP
Identifiers
Aliases	GSAP, PION, Protein pigeon homolog, gamma-secretase activating protein
External IDs	OMIM: 613552 MGI: 2442259 HomoloGene: 45504 GeneCards: GSAP
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q11.23 Start 77,310,751 bp[1] End 77,416,349 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 A3 Start 21,391,253 bp[2] End 21,520,130 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube monocyte spleen right lung visceral pleura right lobe of thyroid gland secondary oocyte upper lobe of left lung left lobe of thyroid gland appendix Top expressed in right lung spermatid right lung lobe left lobe of liver proximal tubule spleen carotid body left lung lobe blood olfactory bulb More reference expression data BioGPS n/a
Gene ontology Molecular function amyloid-beta binding protein binding Cellular component trans-Golgi network Golgi apparatus Biological process regulation of proteolysis positive regulation of amyloid-beta formation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 54103 212167 Ensembl ENSG00000186088 ENSMUSG00000039934 UniProt A4D1B5 Q3TCV3 RefSeq (mRNA) NM_017439 NM_001350896 NM_001350897 NM_001350898 NM_001350899 NM_001350900 NM_001350901 NM_175437 NM_001359876 NM_001359877 RefSeq (protein) NP_059135 NP_001337825 NP_001337826 NP_001337827 NP_001337828 NP_001337829 NP_001337830 NP_780646 NP_001346805 NP_001346806 Location (UCSC) Chr 7: 77.31 – 77.42 Mb Chr 5: 21.39 – 21.52 Mb PubMed search [3] [4]
Wikidata
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Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.^[5]

Gene

The human PION gene is located on the long (q) arm of chromosome 7 at band 11.23, from base pair 76,778,007 to base pair 76,883,653.^[6] Highly conserved PION orthologs have been identified in most vertebrates for which complete genome data are available.^[7] More distantly related orthologs are also expressed in insects including the pigeon gene in Drosophila melanogaster that when mutated produces the "pigeon" phenotype. The name of the human PION gene derives the corresponding Drosophila gene.

Protein

The transcribed human pigeon homolog protein is 854 amino acid residues in length.^[8] A 16 kDa fragment (GSAP-16K) derived from 121 residues from the C-terminus region of the full length protein is known as the γ-secretase activating protein (GSAP).^[9]

Function

γ-secretase activating protein (GSAP) increases β-amyloid production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein (APP).^[9] By binding to both the γ-secretase enzyme and its APP substrate, GSAP increases the affinity and the selectivity of the enzyme for this particular substrate.

Therapeutic target for Alzheimer's disease

The activating function of GSAP can be inhibited by the anticancer drug imatinib (Gleevec) which in turn prevents γ-secretase from converting APP into plaque forming β-amyloid without affecting the other functions of γ-secretase. Imatinib itself does not get into the brain^[10] so imatinib could not be used as an AD therapeutic. However it may be possible to identify imatinib-like drugs that do get into the brain. Hence GSAP represents a potential therapeutic target for the treatment of Alzheimer's disease (AD).^[9]

The drug semagacestat in contrast to imatinib, works by directly inhibiting the γ-secretase. While semagacestat reduces β-amyloid plaque formation in AD patients, γ-secretase is also needed to make other important proteins.^[11] The failure of semagacestat to improve the cognitive function of AD patients may be due to its non-selective blockade of γ-secretase. The more selective blockade of γ-secretase provided by inhibiting GSAP may make GSAP a more efficacious and safer drug target than γ-secretase.^[9]

Discovery

The PION gene was originally discovered through a large scale genome sequencing effort.^[12] However the function of the PION gene product remained a mystery. In the laboratory of Paul Greengard, a screen of compounds that could inhibit the formation of β-amyloid identified imatinib,^[13] however it was not immediately known how it accomplished this. Later it was discovered by Greengard's lab that imatinib inhibited the function of GSAP and that GSAP in turn functions as an activator of γ-secretase.^[9]

References

Further reading