ABSTRACT
After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble "sickness behavior," the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to "reboot." In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.
Subject(s)
Autonomic Nerve Block/methods , COVID-19/complications , Stellate Ganglion/surgery , Adult , COVID-19/surgery , Female , Humans , SARS-CoV-2 , Post-Acute COVID-19 SyndromeABSTRACT
Mutations that perturb the function of photoreceptor CNG (cyclic nucleotide-gated) channels are associated with several human retinal disorders, but the molecular and cellular mechanisms leading to photoreceptor dysfunction and degeneration remain unclear. Many loss-of-function mutations result in intracellular accumulation of CNG channel subunits. Accumulation of proteins in the ER (endoplasmic reticulum) is known to cause ER stress and trigger the UPR (unfolded protein response), an evolutionarily conserved cellular programme that results in either adaptation via increased protein processing capacity or apoptotic cell death. We hypothesize that defective trafficking of cone photoreceptor CNG channels can induce UPR-mediated cell death. To test this idea, CNGA3 subunits bearing the R563H and Q655X mutations were expressed in photoreceptor-derived 661W cells with CNGB3 subunits. Compared with wild-type, R563H and Q655X subunits displayed altered degradation rates and/or were retained in the ER. ER retention was associated with increased expression of UPR-related markers of ER stress and with decreased cell viability. Chemical and pharmacological chaperones {TUDCA (tauroursodeoxycholate sodium salt), 4-PBA (sodium 4-phenylbutyrate) and the cGMP analogue CPT-cGMP [8-(4-chlorophenylthio)-cGMP]} differentially reduced degradation and/or promoted plasma-membrane localization of defective subunits. Improved subunit maturation was concordant with reduced expression of ER-stress markers and improved viability of cells expressing localization-defective channels. These results indicate that ER stress can arise from expression of localization-defective CNG channels, and may represent a contributing factor for photoreceptor degeneration.
Subject(s)
Cyclic Nucleotide-Gated Cation Channels/genetics , Endoplasmic Reticulum/physiology , Retinal Cone Photoreceptor Cells/physiology , Unfolded Protein Response/drug effects , Animals , Cell Death/drug effects , Cell Line , Cell Membrane/metabolism , Cyclic GMP/analogs & derivatives , Cyclic GMP/pharmacology , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/metabolism , Humans , Mice , Molecular Chaperones/pharmacology , Protein Transport/drug effects , Transcription Factor CHOP/metabolismABSTRACT
Homer protein expression is dependent in part on neuronal activity and sleep. Homer1a differs in function from Homer1bc although both are involved in synaptic scaffolding. The effects of sleep loss, time of day and afferent activity on these molecules were investigated. Rats were sacrificed at the midpoint of either their activity or sleep phases and RNA was prepared from somatosensory cortex samples. Homer1a and 1bc mRNA levels were determined by real time PCR. There were greater amounts of both Homer1a and 1bc in night time samples. In controls, there was more Homer1bc than 1a both day and night. Sleep loss upregulated Homer1a in the morning but not at night. Homer1bc was much less affected by manipulations of sleep. Thus, Homer1a may be a state- and activity-dependent synaptic scaling factor.
