Tear down this wall: phosphorylation regulates the internal interfaces of postsynaptic condensates.

Can the fusion/fission of biomolecular condensates be regulated in cells? In a recent study, Wu et al. show that phosphorylation of a key scaffold protein that drives condensates in postsynaptic densities modulates the apparent miscibility of underlying components, thus enabling intracondensate demixing-to-mixing transitions.

Proliferative arrest induces neuron differentiation and innate immune responses in control and Creutzfeldt-Jakob Disease agent infected rat septal neurons.

Rat post-mitotic septal (SEP) neurons, engineered to conditionally proliferate at 33°C, differentiate when arrested at 37.5°C and can be maintained for weeks without cytotoxic effects. Nine independent cDNA libraries were made to follow arrest-induced neural differentiation and innate immune responses in normal (Nl) uninfected and CJ agent infected SEP cells. Proliferating Nl versus latently infected (CJ-) cells showed few RNA-seq differences. However arrest induced major changes. Normal cells displayed a plethora of anti-proliferative transcripts. Additionally, known neuron differentiation transcripts, e.g., Agtr2, Neuregulin-1, GDF6, SFRP4 and Prnp were upregulated. These Nl neurons also displayed many activated IFN innate immune genes, e.g., OAS1, RTP4, ISG20, GTB4, CD80 and cytokines, complement, and clusterin (CLU) that binds to misfolded proteins. In contrast, arrested highly infectious CJ+ cells (10 logs/gm) downregulated many replication controls. Furthermore, arrested CJ+ cells suppressed neuronal differentiation transcripts, including Prnp which is essential for CJ agent infection. CJ+ cells also enhanced IFN stimulated pathways, and analysis of the 342 CJ+ unique transcripts revealed additional innate immune and anti-viral-linked transcripts, e.g., Il17, ISG15, and RSAD2 (viperin). These data show: 1) innate immune transcripts are produced by normal neurons during differentiation; 2) CJ infection can enhance and expand anti-viral responses; 3) latent CJ infection epigenetically imprints many proliferative pathways to thwart complete arrest. CJ+ brain microglia, white blood cells and intestinal myeloid cells with shared transcripts may be stimulated to educe latent CJD infections that can be clinically silent for >30 years.

Synapsin condensation controls synaptic vesicle sequestering and dynamics.

Neuronal transmission relies on the regulated secretion of neurotransmitters, which are packed in synaptic vesicles (SVs). Hundreds of SVs accumulate at synaptic boutons. Despite being held together, SVs are highly mobile, so that they can be recruited to the plasma membrane for their rapid release during neuronal activity. However, how such confinement of SVs corroborates with their motility remains unclear. To bridge this gap, we employ ultrafast single-molecule tracking (SMT) in the reconstituted system of native SVs and in living neurons. SVs and synapsin 1, the most highly abundant synaptic protein, form condensates with liquid-like properties. In these condensates, synapsin 1 movement is slowed in both at short (i.e., 60-nm) and long (i.e., several hundred-nm) ranges, suggesting that the SV-synapsin 1 interaction raises the overall packing of the condensate. Furthermore, two-color SMT and super-resolution imaging in living axons demonstrate that synapsin 1 drives the accumulation of SVs in boutons. Even the short intrinsically-disordered fragment of synapsin 1 was sufficient to restore the native SV motility pattern in synapsin triple knock-out animals. Thus, synapsin 1 condensation is sufficient to guarantee reliable confinement and motility of SVs, allowing for the formation of mesoscale domains of SVs at synapses in vivo.