PSEN2 Gene

Name	presenilin 2
Description	Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or 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 act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPSEN2 is a key component of the γ‐secretase complex whose function extends beyond mere proteolysis of the amyloid precursor protein. It contributes to the generation of amyloid‐β peptides and, in contrast to its homolog PSEN1, is selectively targeted to specific cellular compartments. For instance, PSEN2‐containing complexes are preferentially localized to mitochondria‐associated endoplasmic reticulum membranes, an arrangement that may reconcile disparate mechanistic hypotheses in Alzheimer’s disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, distinct motifs in PSEN2 direct its intracellular routing to the trans‐Golgi network, recycling endosomes, and late endocytic compartments, thereby dictating substrate specificity and favoring the production of longer, aggregation‐prone Aβ species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in proteolysis, PSEN2 critically modulates intracellular Ca²⁺ homeostasis. FAD‐linked mutations in PSEN2 lower endoplasmic reticulum Ca²⁺ store content and enhance Ca²⁺ transfer at the ER–mitochondrial interface by increasing the frequency of Ca²⁺ hot spots. Such alterations in Ca²⁺ dynamics have been demonstrated both by reduced agonist‐induced Ca²⁺ release and by impaired Ca²⁺ uptake, effects that are more pronounced with pathogenic PSEN2 variants."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in proteolytic processing and Ca²⁺ regulation, PSEN2 influences diverse signaling pathways that affect cell fate and homeostasis. PSEN2 physically interacts with proteins such as CALP/KChIP4, which may modulate ion channel activity, and plays a role in maintaining protein complex stability through interactions with regulators such as ubiquilin. Notably, overexpression of both wild‐type and mutant PSEN2 can trigger pro‐apoptotic cascades via p53 activation and caspase‐3 engagement, while FAD‐associated PSEN2 mutations also impair autophagy by blocking autophagosome–lysosome fusion through reduced recruitment of RAB7; furthermore, PSEN2 is uniquely able to restore PDGF‐linked signaling. Together, these findings underscore the multifaceted functions of PSEN2 that extend well beyond its catalytic role in the γ‐secretase complex."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Estela Area-Gomez, Ad J C de Groof, Istvan Boldogh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2009.090219"}], "href": "https://doi.org/10.2353/ajpath.2009.090219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19834068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19834068"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Caroline Van Cauwenberghe, Christine Van Broeckhoven, Kristel Sleegers "}, {"type": "b", "children": [{"type": "t", "text": "The genetic landscape of Alzheimer disease: clinical implications and perspectives."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/gim.2015.117"}], "href": "https://doi.org/10.1038/gim.2015.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26312828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26312828"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xavier Meckler, Frédéric Checler "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.708297"}], "href": "https://doi.org/10.1074/jbc.M115.708297"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27059953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27059953"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ragna Sannerud, Cary Esselens, Paulina Ejsmont, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2016.05.020"}], "href": "https://doi.org/10.1016/j.cell.2016.05.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27293189"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27293189"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Giancarlo Zatti, Roberta Ghidoni, Laura Barbiero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The presenilin 2 M239I mutation associated with familial Alzheimer's disease reduces Ca2+ release from intracellular stores."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Dis (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nbd.2003.11.002"}], "href": "https://doi.org/10.1016/j.nbd.2003.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15006697"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15006697"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Giancarlo Zatti, Andrea Burgo, Marta Giacomello, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Calcium (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ceca.2006.03.002"}], "href": "https://doi.org/10.1016/j.ceca.2006.03.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16620965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16620965"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lucia Brunello, Enrico Zampese, Cristina Florean, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1582-4934.2009.00755.x"}], "href": "https://doi.org/10.1111/j.1582-4934.2009.00755.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19382908"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19382908"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Enrico Zampese, Cristina Fasolato, Maulilio J Kipanyula, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1100735108"}], "href": "https://doi.org/10.1073/pnas.1100735108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21285369"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21285369"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Riccardo Filadi, Elisa Greotti, Gabriele Turacchio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.05.013"}], "href": "https://doi.org/10.1016/j.celrep.2016.05.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27239030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27239030"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yuichi Morohashi, Noriyuki Hatano, Susumu Ohya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M200897200"}], "href": "https://doi.org/10.1074/jbc.M200897200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11847232"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11847232"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Cristine Alves da Costa, Erwan Paitel, Mark P Mattson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.062059899"}], "href": "https://doi.org/10.1073/pnas.062059899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11904448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11904448"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Leann K Massey, Alex L Mah, Diana L Ford, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of ubiquilin decreases ubiquitination and degradation of presenilin proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/jad-2004-6109"}], "href": "https://doi.org/10.3233/jad-2004-6109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15004330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15004330"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "David E Kang, Il Sang Yoon, Emanuela Repetto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500833200"}], "href": "https://doi.org/10.1074/jbc.M500833200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16014629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16014629"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Dirk Beher, Michael Fricker, Alan Nadin, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2019.1596489"}], "href": "https://doi.org/10.1080/15548627.2019.1596489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30892128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30892128"}]}]}]}
Synonyms	CMD1V, AD4, STM2, AD3L, PS2
Proteins	PSN2_HUMAN
NCBI Gene ID	5664
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

PSEN2 has 8,308 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 133 datasets.

Click the + buttons to view associations for PSEN2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

PSEN2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by PSEN2 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PSEN2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of PSEN2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of PSEN2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of PSEN2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of PSEN2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PSEN2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving PSEN2 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of PSEN2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PSEN2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PSEN2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of PSEN2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of PSEN2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of PSEN2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with PSEN2 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with PSEN2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with PSEN2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of PSEN2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of PSEN2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of PSEN2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with PSEN2 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of PSEN2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing PSEN2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing PSEN2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing PSEN2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with PSEN2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with PSEN2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing PSEN2 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of PSEN2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with PSEN2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with PSEN2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with PSEN2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with PSEN2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of PSEN2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by PSEN2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving PSEN2 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving PSEN2 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with PSEN2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with PSEN2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with PSEN2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.