Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling

Abstract

Homeostatic scaling in neurons involve substantial proteome remodelling. Although dynamic changes to the proteome have been attributed to either translational or degradative control individually, there remains a lack of insight towards understanding how the interplay between translation and degradation modules effectuate cellular proteostasis during scaling. Here, we report that a mutual co-dependence of the two apparatus drive synaptic homeostasis in an RNA-dependent manner. We observed that abrogation of either translation or proteasomal activity prevents homeostasis and delineated the spatial features of their association. Members of the translation apparatus such as eIF4E, active forms of p70S6 kinase and miRISC-associated MOV10 were found to remain spatially linked with subunits of the catalytically active 26S proteasome subunits such as Rpt1, Rpt3, Rpt6, α7 and E3 ligase Trim32 on polysomes. We identified that paradigms of chronic downscaling involve miRISC remodelling and entails the degradation of MOV10 via the mTOR-dependent translation of Trim32. miRISC remodelling alone is sufficient to invoke downscaling through the removal of post-synaptic AMPA receptors. Our finding proposes a multifaceted model, where synaptic scaling is regulated by compositional changes in the miRISC via protein-synthesis-driven protein degradation.

The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression

“…TRIM32, the human ortholog of thin , is required for synaptic down-scaling in cultured hippocampal rat neurons ( Srinivasan et al, 2020 ), as well as long-term potentiation in hippocampal mouse brain slices ( Ntim et al, 2020 ), implying a broader role of this E3 ubiquitin ligase in synaptic plasticity. TRIM32 has been implicated in various neurological disorders, such as depression ( Ruan et al, 2014 ), Alzheimer’s disease ( Yokota et al, 2006 ), autism spectrum disorder ( Lionel et al, 2014 ; Ruan et al, 2014 ), or attention deficit hyperactivity disorder ( Lionel et al, 2011 ).…”

The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression

“…Trim32, the human ortholog of thin, is required for synaptic downscaling in cultured hippocampal rat neurons 46 , as well as long-term potentiation in hippocampal mouse slices 47 , implying a broader role of this E3 ubiquitin ligase in synaptic plasticity. Trim32 has been implicated in various neurological disorders, such as depression 48 , Alzheimer's Disease 49 , Autism Spectrum Disorder 48,50 , or attention deficit hyperactivity disorder 51 .…”

Transcriptomic analysis identifies synapse-enriched lncRNAs required for excitatory synapse development and fear memory

“…Pantr1 knockdown in CA1 neurons had no effect on contextual fear memory (Figure 7). We therefore speculate that Pantr1 could be involved in other forms of protein synthesis-dependent plasticity (Srinivasan et al, 2021) rather than Hebbian plasticity. As SynLAMP functions as a positive regulator of activity-dependent translation (Figure 5), and SynLAMP RNAi disrupts memory consolidation, SynLAMP-mediated dendritic protein synthesis could be a link to contextual fear memory (Figures 5 and 7).…”

“…). mEPSC amplitude determines synaptic strength and is a direct readout of the abundance of AMPARs on the postsynaptic membrane(O'Brien et al, 1998;Srinivasan et al, 2021). The observed reduction in mEPSC amplitude therefore prompted us to measure AMPAR levels on the postsynaptic surface (sAMPARs) following knockdown of SynLAMP, Pantr1 and Pvt1.…”