Fusogen-mediated neuron−neuron fusion disrupts neural circuit connectivity and alters animal behavior

Abstract

The 100-y-old neuron doctrine from Ramón y Cajal states that neurons are individual cells, rejecting the process of cell−cell fusion in the normal development and function of the nervous system. However, fusogens—specialized molecules essential and sufficient for the fusion of cells—are expressed in the nervous system of different species under conditions of viral infection, stress, or disease. Despite these findings, whether the expression of fusogens in neurons leads to cell−cell fusion, and, if so, whether this affects neuronal fate, function, and animal behavior, has not been explored. Here, using Caenorhabditis elegans chemosensory neurons as a model system, we provide proof-of-principle that aberrant expression of fusogens in neurons results in neuron−neuron fusion and behavioral impairments. We demonstrate that fusion between chemoattractive neurons does not affect the response to odorants, whereas fusion between chemoattractive and chemorepulsive neurons compromises chemosensation. Moreover, we provide evidence that fused neurons are viable and retain their original specific neuronal fate markers. Finally, analysis of calcium transients reveals that fused neurons become electrically coupled, thereby compromising neural circuit connectivity. Thus, we propose that aberrant expression of fusogens in the nervous system disrupts neuronal individuality, which, in turn, leads to a change in neural circuit connectivity and disruption of normal behavior. Our results expose a previously uncharacterized basis of circuit malfunction, and a possible underlying cause of neurological diseases.

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…Indeed, as aging was associated with an increased number of fused neurons, syncytia formation may be neuroprotective by averting the premature elimination of neuronal cells ( Kemp et al. ; Hornik et al., 2014 ; Giordano-Santini et al., 2020 ).…”

“…; Hornik et al., 2014 ). Recent studies in Caenorhabditis elegans (C. elegans) reported fusogen-mediated neuron-neuron and neuron-glia mergers, suggesting that syncytia formation may drive neurocognition ( Alexander et al., 2014 ; Giordano-Santini et al., 2020 ). Moreover, multinucleated neurons in the supraoptic nucleus were demonstrated in patients with pneumonia, a disease often associated with respiratory viruses, likely implicating virus-usurped host fusogens in this pathology ( Ishunina et al., 2000 ).…”

The SARS-CoV-2 spike (S) and the orthoreovirus p15 cause neuronal and glial fusion

“…Fused neurons can result in compromised neuronal circuitry and altered animal behavior, as previously shown for C. elegans chemosensory neurons that ectopically express endogenous fusogens 31 . Our results demonstrate that neurons expressing viral fusogens acquire the capacity to fuse, potentially compromising their functional circuit properties while remaining viable.…”

Cell Fusion as a Link between the SARS-CoV-2 Spike Protein, COVID-19 Complications, and Vaccine Side Effects

“…32,33 How such coupling could also contribute to the loss of smell, a common symptom of COVID-19, can be gleaned from experiments in the nematode C. elegans in which fusing two functionally different chemosensory neurons impaired chemosensation. 34 In humans, the fusion between neurons and glial cells, which surround neuronal bodies, has been proposed to explain the origin and persistence of the neuropathic pain that can last for months after the acute phase of herpes zoster (shingles). 35 This fusion has been detected in a patient affected by shingles, 36 confirmed in a human xenograft model of this disease, 37 and accidentally discovered in an unrelated mouse model in which cortical neurons were infected with a retrovirus pseudotyped with VSV-G, the fusogen of vesicular stomatitis virus.…”