Presenilin enhancer protein 2 (PEN-2) (PEN-2)

Presenilin enhancer protein 2 (PEN-2) is a critical 101-amino acid integral membrane subunit of the gamma-secretase complex, an aspartyl protease that cleaves various type I transmembrane proteins [1][2]. PEN-2 is essential for the endoproteolytic activation of presenilin and the assembly of the mature, functional protease complex [3]. While gamma-secretase is present in multiple cellular compartments, its localization on the lysosomal membrane is particularly significant for maintaining lysosomal acidification and supporting autophagic flux [4]. Dysregulation of PEN-2-containing complexes is a hallmark of Alzheimer's disease, where it facilitates the production of neurotoxic amyloid-beta peptides from the amyloid precursor protein (APP) [5]. Beyond neurodegeneration, mutations in the PSENEN gene, which encodes PEN-2, are linked to skin disorders such as acne inversa and Dowling-Degos disease [6]. Therapeutic efforts have largely focused on gamma-secretase inhibitors (GSIs) and modulators (GSMs) to reduce amyloid-beta levels, though clinical trials have been hampered by toxicities arising from the inhibition of Notch signaling [7]. Recent research also explores the role of lysosomal PEN-2 in metabolic signaling and its potential as a target for modulating cellular degradation pathways [8].

Other names

PEN2PSENENPresenilin enhancer 2 homologMSTP064

Inhibition or modulation of the gamma-secretase complex to prevent the cleavage of substrates such as Amyloid Precursor Protein (APP) and Notch, or to shift the cleavage site of APP to produce shorter, less toxic amyloid peptides.