Presenilin-2 is a protein that (in humans) is encoded by the PSEN2 gene. [5]
Presenilin-2 is a protein that (in humans) is encoded by the PSEN2 gene. [5]
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. [6]
In melanocytic cells PSEN2 gene expression may be regulated by MITF. [7]
PSEN2 has been shown to interact with:
Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 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.
Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.
APH-1 is a protein gene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.
Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.
Neurogenic locus notch homolog protein 2 is a protein that in humans is encoded by the NOTCH2 gene.
Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.
Laminin subunit alpha-1 is a protein that in humans is encoded by the LAMA1 gene.
Calsenilin is a protein that in humans is encoded by the KCNIP3 gene.
Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.
Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.
Filamin B, beta (FLNB), also known as Filamin B, beta , is a cytoplasmic protein which in humans is encoded by the FLNB gene.
Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.
Plakophilin-4 is a protein that in humans is encoded by the PKP4 gene.
Integral membrane protein 2B is a protein that in humans is encoded by the ITM2B gene.
Amyloid beta A4 precursor protein-binding family B member 2 is a protein that in humans is encoded by the APBB2 gene.
Amyloid beta A4 precursor protein-binding family B member 3 is a protein that in humans is encoded by the APBB3 gene.
Dedicator of cytokinesis protein 3 (Dock3), also known as MOCA and PBP, is a large protein encoded in the human by the DOCK3 gene, involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock3 specifically activates the small G protein Rac.
Collagen alpha-1(XXV) chain is a protein that in humans is encoded by the COL25A1 gene.
Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.
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