Presenilin-1 (PSEN1) is a part of the gamma-secretase complex. It has several interacting substrates, such as amyloid precursor protein (APP), Notch, adhesion proteins, and beta-catenin. PSEN1 is involved in multiple processes, including Notch signaling, β-cadherin processing, and calcium metabolism, and is of great significance in neurodegeneration [1,3].

PSEN1 has been extensively studied in neurodegenerative diseases. Over 300 PSEN1 mutations have been discovered. In addition to the classical early-onset Alzheimer's disease (EOAD), these mutations are associated with various atypical AD or non-AD phenotypes, like frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), or spastic paraparesis (SP). Some mutations are also related to non-neurodegenerative phenotypes, such as acne inversa and dilated cardiomyopathy [1]. In an AD-CO model created from iPSCs with PSEN1 mutations, the model developed AD-specific markers but also showed tissue patterning defects and altered development [2].

In conclusion, PSEN1 plays a crucial role in the gamma-secretase complex and is involved in multiple biological processes. The study of PSEN1 mutations through various research models, like the AD-CO model, has revealed its associations with a wide range of neurodegenerative and non-neurodegenerative phenotypes, deepening our understanding of the underlying disease mechanisms [1,2].