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.

Role of microglia in stress-induced alcohol intake in female and male mice.

Rates of alcohol use disorder (AUD) have escalated in recent years, with a particular increase among women. Women are more susceptible to stress-induced alcohol drinking, and preclinical data suggest that stress can increase alcohol intake in female rodents; however, a comprehensive understanding of sex-specific neurobiological substrates underlying this phenomenon is still emerging. Microglia, the resident macrophages of the brain, are essential for reshaping neuronal processes, and microglial activity contributes to overall neuronal plasticity.

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.