PSEN1

PSEN1, also known as presenilin-1, is a protein encoded by the PSEN1 gene in humans. The gene is located on chromosome 14 at 14q24.3. PSEN1 encodes a multi-pass transmembrane aspartyl protease that forms the catalytic core of the gamma-secretase complex, a multi-subunit protease responsible for intramembrane cleavage of several type I transmembrane proteins.

In the gamma-secretase complex, presenilin-1 provides the proteolytic activity and interacts with other components, including nicastrin, APH1 (presenilin enhancer 1) isoforms, and PEN2. The complex cleaves the amyloid precursor protein (APP) to generate amyloid-β peptides, and it also mediates the Notch signaling pathway by releasing the Notch intracellular domain. This dual role links PSEN1 to processes in development and neuronal function.

Mutations in PSEN1 are a major cause of autosomal dominant early-onset familial Alzheimer's disease (FOAD). Pathogenic variants typically alter gamma-secretase activity, often increasing the production or promo­tion of the aggregation-prone Aβ42 peptide relative to Aβ40, promoting amyloid plaque formation and neurodegeneration. PSEN1 mutations show substantial clinical and phenotypic variability but commonly lead to disease onset in the 30s to 60s.

Biochemically, presenilin-1 is a roughly 467-amino-acid protein with multiple transmembrane domains; the aspartate residues essential for catalysis are D257 and D385. Mouse models indicate that complete loss of PSEN1 is lethal, while partial loss yields milder effects, reflecting its essential role in development and cellular signaling.

Therapeutically, targeting gamma-secretase has been challenging due to Notch-related side effects, guiding research toward substrate-selective modulators rather than broad inhibitors.