BRIEF RESEARCH REPORT article
Front. Mol. Biosci.
Sec. Cellular Biochemistry
This article is part of the Research TopicThe Axon and its Autophagy-Driven Homeostatic Control: Implications for the Onset of Human Neurodegenerative DiseasesView all 3 articles
Differential roles for CLA-1L and UNC-10 in endosomal maturation and peptide release at C. elegans synapses impacting lifespan
Provisionally accepted
- University of Illinois Chicago Department of Biological Sciences, Chicago, United States
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C. elegans encode two synaptic proteins linked to the Rim/Piccolo/Fife-family, through conserved motifs: 1) Clarinet (CLA-1), has 3 isoforms, (short(S), medium(M) and long(L)) that are anchored at the active zone through a common C-terminal domain and 2) UNC-10/Rim that is also highly enriched at the presynaptic density. Both the cla-1 and unc-10 mutants have demonstrable effects on synaptic transmission and in combination produce a synergistic impact that virtually eliminates synaptic transmission and that has yet to be fully understood. Recently, CLA-1L and UNC-10 were shown to differentially regulate key active zone components, culminating in reduced Ca2+ channels and UNC-13 levels, but these changes cannot account for the severity of the release defects in the double mutants. CLA-1L extends far beyond the synaptic active zone and has been implicated in recycling of the key autophagy protein ATG-9. In this study, we show that cla-1L and unc-10 mutants negatively impact proteins involved in endocytic processing (ITSN-1 and AP-2) and endolysosomal maturation (RAB-5 and RAB-7). These abnormalities correlate with an accumulation of synaptic pleiomorphic vesicles by EM, in both cla-1L and unc-10 mutants. In addition, unc-10 mutants accumulate dense core vesicles, due to a dramatic reduction in neuropeptide release. These observations are accompanied by significant decreases in lifespan in both cla-1L and unc-10 mutants, which are exacerbated in the double mutants. Together these data suggest that the cumulative effects on synaptic transmission that result from distinct roles of CLA-1L and UNC-10 have an impact on survival.
Keywords: RIM, Cla-1, C.elegans, Endosome maturation, neuropeptide release
Received: 28 Jul 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 Krout, Miciulis and Richmond. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Janet E Richmond, jer@uic.edu
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