Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery

Neuronal extracellular vesicles (EVs) carry cargoes that are important in intercellular signaling and disease, but how and where cargoes are sorted into EVs remains unclear. Here, we identified a new role for canonical clathrin-mediated endocytic machinery in controlling EV cargo traffic in Drosophila neurons. Endocytic mutants, including nervous wreck (nwk), Shibire/Dynamin, and AP-2, exhibit local depletion of multiple cargoes in presynaptic EV donor terminals as well as in EVs. Accordingly, nwk mutants phenocopy synaptic plasticity defects associated with loss of the EV cargo Synaptotagmin-4, and suppress lethality upon overexpression of the EV cargo Amyloid Precursor Protein. These EV defects are genetically separable from canonical functions of endocytic proteins in synaptic vesicle recycling and synaptic growth. Nwk opposes the endosomal retromer complex to regulate EV cargo levels, and acts upstream of dynactin-mediated retrograde axonal transport. Our data suggest a novel molecular mechanism that protects EV cargoes from local depletion at synapses.

Rab10 regulates the sorting of internalised TrkB to retrograde axonal transport

The extreme, complex morphology of neurons provides an unrivalled model to study the coordination between local signalling and long-range cell responses. A cogent example is provided by the binding of brain-derived neurotrophic factor (BDNF) to its receptor TrkB, which triggers signalling cascades at axon terminals that result in responses at the level of the cell body, including modulation of gene expression. Retrograde propagation of these critical signals relies on the sorting of activated TrkB receptors to retrograde axonal transport organelles termed signalling endosomes. In this work, we show that the small GTPase Rab10 is critical for the sorting of activated TrkB receptors to axonal retrograde carriers and the propagation of neurotrophin signalling from the axon terminal to the soma. Moreover, our data indicate that Rab10 defines a novel class of axonal organelles that are mobilised towards the axon terminal upon BDNF stimulation, thus enabling the axon to dynamically adjust the retrograde signalling flow to changes in BDNF availability at the synapse.

Neuropathogenesis of Neurotropic Viruses

Neuropathogenesis can simply be defined as the mechanisms of the origin, development and progression of the CNS disease which comprises both neuroinvasion and neurovirulence. Viruses that have the ability to induce neuropathogenesis are called neurotropic pathogens. The exact mechanisms of neuropathogenesis is still unknown, however, the following pathways have been proposed and include retrograde axonal transport, hematogenous spread from the peripheral blood to the cerebral blood vessesls across blood brain barrier, direct invasion of the endothelial cells and endocytosis across the viral receptors. The main neurotropic viral families are picornaviruses, arboviruses, paramixoviruses, arenaviruses and herpes family viruses. In this review, the main mechanisms of neuropathogenesis of the neurotropic members of these viral families was discussed

Molecular and cellular mechanisms of central nervous system alteration in COVID-19

The ongoing coronavirus disease 2019 (COVID-19) pandemic dictates the need to study the molecular and cellular mechanisms of interaction between the pathogen and the human body. The manifestation of neurological symptoms in some patients with COVID-19 is a problem for neuroscientists due to the insufficiently understood pathomorphogenesis of the disease. This review systematizes the literature data reflecting the ways of penetration of SARS-CoV-2 into the brain, features of its interaction with neurons, neuroglia, and immune cells. It has been shown that the main mechanisms of SARS-CoV-2 neuroinvasion are presumably retrograde axonal transport along the fibers of the olfactory and vagus nerves; penetration through the damaged blood-brain barrier (BBB) or migration of immunocompetent cells containing viral particles through the intact BBB. It was found that virusinducible neuronal death is caused not only by a direct cytotoxic effect, but also due to dysregulation of the reninangiotensin system of the brain and the release of a large amount of inflammatory cytokines as a manifestation of a “cytokine storm”. The participation of neuroglial cells in the initiation and maintenance of neuroinflammatory and neurodegenerative processes due to the activation of their proinflammatory phenotype has been demonstrated. The role of mast cells in antiviral defense mechanisms and inflammatory reactions is discussed.

COVID-19-associated meningoencephalitis treated with intravenous immunoglobulin

A 40-year-old man presented with altered mental status after a recenthospitalisation for COVID-19 pneumonia. Cerebrospinal fluid (CSF) analysis showed lymphocytosis concerning for viral infection. The CSF PCR for SARS-CoV-2 was negative, yet this could not exclude COVID-19 meningoencephalitis. During hospitalisation, the patient’s mentation deteriorated further requiring admission to the intensive care unit (ICU). Brain imaging and electroencephalogram (EEG) were unremarkable. He was, thus, treated with intravenous immunoglobulin (IVIg) for 5 days with clinical improvement back to baseline. This case illustrates the importance of considering COVID-19’s impact on the central nervous system (CNS). Haematogenous, retrograde axonal transport, and the effects of cytokine storm are the main implicated mechanisms of CNS entry of SARS-CoV-2. While guidelines remain unclear, IVIg may be of potential benefit in the treatment of COVID-19-associated meningoencephalitis.

A Conserved Role for Vezatin Proteins in Cargo-Specific Regulation of Retrograde Axonal Transport

Active transport of organelles within axons is critical for neuronal health. Retrograde axonal transport, in particular, relays neurotrophic signals received by axon terminals to the nucleus and circulates new material among en passant synapses. A single motor protein complex, cytoplasmic dynein, is responsible for nearly all retrograde transport within axons: its linkage to and transport of diverse cargos is achieved by cargo-specific regulators. Here, we identify Vezatin as a conserved regulator of retrograde axonal transport. Vertebrate Vezatin (Vezt) is required for the maturation and maintenance of cell-cell junctions and has not previously been implicated in axonal transport. However, a related fungal protein, VezA, has been shown to regulate retrograde transport of endosomes in hyphae. In a forward genetic screen, we identified a loss-of-function mutation in the Drosophila vezatin-like (vezl) gene. We here show that vezl loss prevents a subset of endosomes, including signaling endosomes containing activated BMP receptors, from initiating transport out of motor neuron terminal boutons. vezl loss also decreases the transport of endosomes and dense core vesicles, but not mitochondria, within axon shafts. We disrupted vezt in zebrafish and found that vezt loss specifically impairs the retrograde axonal transport of late endosomes, causing their accumulation in axon terminals. Our work establishes a conserved, cargo-specific role for Vezatin proteins in retrograde axonal transport.