PSEN1/PS1 Cancer Research Results

PSEN1 - Presenilin-1

Abbreviation: PSEN1, PS1

Type: Intramembrane aspartyl protease / catalytic subunit of the γ-secretase complex

Function: PSEN1 is the principal catalytic component of the γ-secretase complex, which performs intramembrane proteolysis of numerous substrates including amyloid precursor protein (APP) and NOTCH receptors. APP cleavage by PSEN1-containing γ-secretase generates amyloid-β peptides including Aβ40 and Aβ42. PSEN1 also regulates cellular signaling, membrane-protein processing, calcium homeostasis, and neuronal function.

Cancer: ↕ Context-dependent. PSEN1-dependent γ-secretase activity can promote oncogenic signaling through cleavage and activation of NOTCH receptors and other substrates. γ-Secretase inhibition can suppress NOTCH-driven proliferation, survival, stemness, and tumor progression in selected cancers, although PSEN1 function varies substantially according to tumor type and substrate context.

Alzheimer's Disease: ↕ Pathogenic alteration of PSEN1 function is a major cause of autosomal-dominant early-onset Alzheimer's disease. Disease-causing PSEN1 mutations alter γ-secretase processivity and commonly increase the relative production of longer, aggregation-prone Aβ species, particularly the Aβ42/Aβ40 ratio. Many pathogenic mutations reduce overall γ-secretase cleavage efficiency, so Alzheimer's disease is better characterized by abnormal PSEN1 function than by a simple increase or decrease in PSEN1 expression.