Monoamines such as noradrenaline and serotonin are stored in secretory vesicles and released by exocytosis. Two related monoamine transporters, VMAT1 and VMAT2, mediate vesicular transmitter uptake. Previously we have reported that in the rat pheochromocytoma cell line PC 12 VMAT1, localized to peptide-containing secretory granules, is controlled by the heterotrimeric G-protein Go(2). We now show that in BON cells, a human serotonergic neuroendocrine cell line derived from a pancreatic tumor expressing both transporters on large, dense-core vesicles, VMAT2 is even more sensitive to G-protein regulation than VMAT1. The activity of both transporters is only downregulated by Galphao(2), whereas comparable concentrations of Galphao(1) are without effect. In serotonergic raphe neurons in primary culture VMAT2 is also downregulated by pertussis toxin-sensitive Go(2). By electron microscopic analysis from prefrontal cortex we show that VMAT2 and Galphao(2) associate preferentially to locally recycling small synaptic vesicles in serotonergic terminals. In addition, Go(2)-dependent modulation of VMAT2 also works when using a crude synaptic vesicle preparation from this brain area. We conclude that regulation of monoamine uptake by the heterotrimeric G proteins is a general feature of monoaminergic neurons that controls the content of both large, dense-core and small synaptic vesicles.

C3 exoenzyme from Clostridium botulinum, specifically ADP-ribosylates small GTP-binding proteins RhoA, B, and C. ADP-ribosylation causes functional inactivation of Rho proteins resulting in cessation of the complete downstream signaling. Rho proteins are general regulators of a lot of essential cellular functions, among others, the neuronal growth cone. Rho activation, triggered by neuronal injury, inhibits neuronal repair mechanisms. To prevent the detrimental effect of active Rho in the recovery of injured neuronal systems, C3 has become a promising drug to inactivate RhoA in neurons. During the advancement of C3 to a drug candidate, it was found that ADP-ribosyltransferase activity of C3, in fact, is not essential for axonal and dendritic growth and branching. Rather, a peptide fragment of C3 covering the surface exposed ARTT loop from C3 (C3(154-182) peptide) is sufficient to induce growth and branching of neurons comparable to the effect of full-length C3. Whereas full-length C3 also acts on astrocytes and microglia to induce-at least in an in vitro model-inflammation and glial scar formation, C3(154-182) peptide is inert and seems only to act on neurons. In addition to its axono- and dendritotrophic effects on cultured primary hippocampal neurons, C3(154-182) peptide enhanced functional recovery and regeneration in a mouse model of spinal cord injury. Thus, in a proof-of-principle experiment, C3 peptide was shown to be efficacious in post-traumatic neuro-regeneration.

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We prospectively recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3%. Seropositivity was strongly associated with abnormalities of fetal development including intrauterine growth retardation. This finding indicates that these autoantibodies may be clinically useful developmental biomarkers and/or even directly participate in the disease process, thus being amenable to antibody-targeting interventional strategies in the future.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virusneutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy. .

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