Cell type- and neuronal differentiation-dependent <i>MME</i> 5′UTR splice variants with distinct translational outputs in human cells

Neprilysin (NEP) is a major enzyme that degrades amyloid β-peptide (Aβ) in the brain. Deficient NEP activity causes Aβ to accumulate, leading to amyloid pathology in Alzheimer's disease. Transcripts from the MME gene encoding NEP comprise seven splice variants (v1, v1bis, v2a, v2b, and v3-5) with different structures in the 5'-untranslated region. We analyzed the expression levels of MME variants in neuronal and non-neuronal cells using real-time PCR and investigated their translational outputs using cells co-transfected with cDNAs of each MME variant and green fluorescent protein. v1 and v1bis were constitutively expressed as major components in both cell types, whereas v2b was preferentially expressed in non-neuronal cells. The translational outputs of v1 and v2b were similar to each other and much higher than those of the other variants. Retinoic acid-induced neuronal differentiation altered the compositional ratios of MME variants and transiently enhanced their translational outputs, which declined in a variant-specific manner with further differentiation. We demonstrated that MME variants show cell type-dependent expression and distinct translational outputs that are sensitive to retinoic acid. Further studies are required to elucidate the molecular mechanisms underlying the post-translational roles of MME variants, such as subcellular localization and local translation.