PSENEN, also known as PEN2 or presenilin enhancer 2, is the smallest subunit of the γ -secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. It is essential for the formation and stabilization of the γ -secretase complex, which is involved in the generation of Aβ peptides in Alzheimer's disease. PSENEN also participates in multiple biological processes including adipocyte differentiation, autophagy-lysosome system regulation, and is involved in several signaling pathways such as Notch signaling [2,3,4].

In knockout studies, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, while intestine-specific knockout of Pen2 impairs its glucose-lowering effects. In Caenorhabditis elegans, knockdown of pen-2 abrogates metformin-induced extension of lifespan, revealing that metformin binds PEN2 and initiates a signaling route intersecting the lysosomal glucose-sensing pathway for AMPK activation [1]. In HeLa knockout cell lines for PSENEN, alterations in the autophagy-lysosome system were observed, including reduced activity of lysosomal enzymes and lysosome number, increased autophagosomes, increased lysosome-autophagosome fusion, and elevated levels of TFEB [2].

In conclusion, PSENEN is crucial for the function of the γ -secretase complex and is involved in various biological processes. Studies using gene knockout models, such as in mice and C. elegans, have revealed its role in metformin-related metabolic regulation and in the autophagy-lysosome system, which may have implications for understanding and treating diseases like diabetes and neurodegenerative disorders [1,2].

References:

1. Ma, Teng, Tian, Xiao, Zhang, Baoding, Zhang, Chen-Song, Lin, Sheng-Cai. 2022. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. In Nature, 603, 159-165. doi:10.1038/s41586-022-04431-8. https://pubmed.ncbi.nlm.nih.gov/35197629/

2. Klein, Marcel, Kaleem, Abuzar, Oetjen, Sandra, Kuhl, Dietmar, Hermey, Guido. 2021. Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system. In Autophagy, 18, 2068-2085. doi:10.1080/15548627.2021.2016232. https://pubmed.ncbi.nlm.nih.gov/34964690/

3. Lee, S M, Jeong, Y H, Kim, H M, Moon, S J, Kang, M J. 2009. Presenilin enhancer-2 (PSENEN), a component of the gamma-secretase complex, is involved in adipocyte differentiation. In Domestic animal endocrinology, 37, 170-80. doi:10.1016/j.domaniend.2009.05.003. https://pubmed.ncbi.nlm.nih.gov/19592191/

4. Serneels, Lutgarde, Bammens, Leen, Zwijsen, An, Chávez-Gutiérrez, Lucía, De Strooper, Bart. 2023. Functional and topological analysis of PSENEN, the fourth subunit of the γ-secretase complex. In The Journal of biological chemistry, 300, 105533. doi:10.1016/j.jbc.2023.105533. https://pubmed.ncbi.nlm.nih.gov/38072061/