Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions.

While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors.

Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions.

While previous studies suggest that many mRNAs contain more than one translation initiation site (TIS), the biological significance of most alternative TISs and their corresponding protein isoforms (proteoforms) remains undetermined. Here we show that alternative translation initiation at a CUG and an AUG TIS in neuronal pentraxin receptor (NPR) mRNA produces two proteoforms, and their relative abundance is regulated by both neuronal activity as well as an adjacent RNA secondary structure. Downstream AUG initiation transforms the N-terminal transmembrane domain into a signal peptide, thereby converting NPR to a secreted factor sufficient to promote synaptic clustering of AMPA-type glutamate receptors.

Regulation of nonsense-mediated mRNA decay in neural development and disease.

Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon but also as a posttranscriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood.