SEZ6L (seizure related 6 homolog like) is a neuronal transmembrane protein of 1024 amino acids containing multiple domains involved in protein-protein interaction and signal transduction 1. The protein functions as a physiological substrate of the Alzheimer's disease protease BACE1, which cleaves SEZ6L near the membrane to produce a soluble ectodomain (sSEZ6L) 2. BACE1 cleavage regulates SEZ6L surface expression on neurons, and levels of sSEZ6L in cerebrospinal fluid serve as markers for BACE1 activity 2. Functionally, SEZ6L plays critical roles in motor coordination and anxiety regulation, as constitutive knockout mice display altered gait, decreased motor coordination, and increased anxiety-like behavior, though spatial learning remains normal 3. In disease contexts, SEZ6L shows clinical significance across multiple neurological conditions. A Met430Ile polymorphism (rs663048) increases lung cancer risk with a combined odds ratio of 3.32 for homozygous variant carriers 4 and improves lung cancer risk prediction models 5. Additionally, SEZ6L variants associate with multiple sclerosis severity outcomes 6, and the gene is upregulated in post-stroke human brain tissue, particularly in astrocytes and oligodendrocyte lineage cells, suggesting roles in neuroprotection and repair 7.