Sez6l, also known as seizure 6-like protein, is a neuronal substrate of the Alzheimer's disease protease BACE1 [1,2,3,5]. It may be involved in multiple biological processes. In the nervous system, it has potential functions related to synaptic function [3]. In addition, its role in diseases like lung cancer has been investigated, with a polymorphic Met430Ile substitution in the gene associated with increased lung cancer risk [4].

In Sez6l constitutive knockout mice, motor phenotypes are observed in adulthood, including gait changes and decreased motor coordination. These mice also display increased anxiety-like behavior, indicating Sez6l's role in regulating motor coordination and curbing anxiety-related behavior [1]. In Niemann-Pick type C disease mouse brains, an enhanced BACE1-cleavage of Sez6l was detected, suggesting that abnormal processing of Sez6l by BACE1 could be part of the disease pathogenesis [3].

In conclusion, Sez6l is an important protein with functions in regulating motor coordination and anxiety-related behavior as revealed by gene knockout mouse models. Its abnormal processing may be involved in diseases such as Niemann-Pick type C disease, and its genetic variation is associated with lung cancer risk. These findings from model-based research contribute to understanding the role of Sez6l in specific biological processes and disease conditions.

References:

1. Ong-Pålsson, Emma, Njavro, Jasenka Rudan, Wilson, Yvette, Munro, Kathryn M, Lichtenthaler, Stefan F. 2021. The β-Secretase Substrate Seizure 6-Like Protein (SEZ6L) Controls Motor Functions in Mice. In Molecular neurobiology, 59, 1183-1198. doi:10.1007/s12035-021-02660-y. https://pubmed.ncbi.nlm.nih.gov/34958451/

2. Dominko, Kristina, Rastija, Ana, Smiljanic, Kosara, Milanovic, Desanka, Hecimovic, Silva. 2022. Amyloid-ß plaque formation and BACE1 accumulation in the brains of a 5xFAD Alzheimer's disease mouse model is associated with altered distribution and not proteolysis of BACE1 substrates Sez6 and Sez6L. In Mechanisms of ageing and development, 207, 111726. doi:10.1016/j.mad.2022.111726. https://pubmed.ncbi.nlm.nih.gov/35998821/

3. Causevic, Mirsada, Dominko, Kristina, Malnar, Martina, Lichtenthaler, Stefan F, Hecimovic, Silva. 2018. BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains. In PloS one, 13, e0200344. doi:10.1371/journal.pone.0200344. https://pubmed.ncbi.nlm.nih.gov/29979789/

4. Gorlov, Ivan P, Meyer, Peter, Liloglou, Triantafillos, Field, John K, Amos, Christopher I. . Seizure 6-like (SEZ6L) gene and risk for lung cancer. In Cancer research, 67, 8406-11. doi:. https://pubmed.ncbi.nlm.nih.gov/17804757/

5. Pigoni, Martina, Wanngren, Johanna, Kuhn, Peer-Hendrik, Müller, Stephan A, Lichtenthaler, Stefan F. 2016. Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. In Molecular neurodegeneration, 11, 67. doi:. https://pubmed.ncbi.nlm.nih.gov/27716410/