Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles are related to Neuron-glia Interactions.
Title: Ferroptosis in Parkinson's disease: glia–neuron crosstalk
Authors: Zhang-Li Wang, Lin Yuan, Wen Li, Jia-Yi Li
Type: Review Article
Iron uptake, storage, efflux, and utilization are essential for maintaining iron homeostasis. Abnormal expression of proteins involved in these processes related to iron homeostasis may cause iron overload and induce subsequent ferroptosis, which is associated with the pathogenesis of neurodegenerative disease.
Crosstalk between glia and neurons underlies the ferroptotic alterations in DA neurons and form a vicious circle in promoting PD pathogenesis.
Possible mechanisms of iron transfer between glia and neurons include exosomes and tunneling nanotubes. They may determine the efficacy of ferroptosis inhibitors and provide a clue for exploring novel therapeutic interventions for PD.
Joint medications with ferroptosis inhibitors and anti-inflammatory medicines may provide a potential strategy for the treatment of PD and related neurodegenerative diseases.
Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.
Access this article: https://doi.org/10.1016/j.molmed.2022.02.003
Title: Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection
Authors: Masha G. Savelieff, Eva L. Feldman, Amro M. Stino
Type: Review Article
The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection.
Access this article: https://doi.org/10.1016/j.nbd.2022.105715
Title: Activated glia cells cause bioenergetic impairment of neurons that can be rescued by knock-down of the mitochondrial calcium uniporter
Authors: Angela Maria Casaril, Athanasios Katsalifis, Rolf M. Schmidt, Carlos Bas-Orth
Type: Short Communication
●Neuronal mitochondrial membrane potential is particularly sensitive to inflammation.
●Neuronal bioenergetic impairment occurs prior to cell death in neuroinflammation.
●Inflammation-induced functional impairment of neuronal mitochondria involves Mcu.
Neuroinflammation is a hallmark of various neurological disorders including autoimmune-, neurodegenerative and neuropsychiatric diseases. In neuroinflammation, activated microglia and astrocytes release soluble mediators such as cytokines, glutamate, and reactive oxygen species that negatively affect neuronal function and viability, and thus contribute to neurodegeneration during disease progression. Therefore, the development of neuroprotective strategies might be important in addition to treating inflammation in these diseases. Mitochondria are promising cellular targets for neuroprotective interventions: They are among the first structures affected in many neuroinflammatory diseases, with mitochondrial impairment ranging from impaired respiratory activity and reduced mitochondrial membrane potential to mitochondrial oxidation and fragmentation. Therefore, we developed a cell culture model that resembles an early state of inflammation-induced neuronal mitochondrial dysfunction preceding neuronal cell death, and can be used to test mito- and neuroprotective strategies. Rat primary cortical neurons were challenged with conditioned medium from mixed primary cultures of rat microglia and astrocytes that had been activated with lipopolysaccharide and ATP. When sublethal amounts of glia-conditioned medium were added to neurons for 24 h, mitochondrial membrane potential and ATP levels were decreased, whereas mitochondrial redox state remained unaffected. Effects on mitochondrial membrane potential and ATP levels were ameliorated by knock-down of the mitochondrial calcium uniporter in neurons. This study suggests that neuronal bioenergetic failure is an early event during neuroinflammation and it identifies the mitochondrial calcium uniporter as a candidate target for neuroprotection in this context.
Access this article: https://doi.org/10.1016/j.bbrc.2022.03.120
Title: Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice
Authors: Savannah M. Rocha, Collin M. Bantle, Tawfik Aboellail, Debotri Chatterjee, Richard J. Smeyne, Ronald B. Tjalkens
Type: Research Article
●Rotenone induces replicable features of Parkinson's Disease pathology in mice.
●Spread of misfolded α-synuclein follows rotenone-induced glial activation.
●Microglia modulate the distribution of protein aggregation in response to rotenone.
●Reactive astrocytes initiate the glial response to rotenone toxicity.
●The progression of rotenone-induced neuropathology is region-specific.
Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson's disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine model of rotenone-induced PD, we therefore investigated the progression of neuroinflammation, protein aggregation and DAn loss in C57Bl/6 mice by exposing animals to 2.5 mg/kg/day rotenone for 14 days, followed by a two-week period where neuroinflammation is allowed to progress. Our results indicate that initial cellular dysfunction leads to increased formation of proteinase K-resistant p129 aggregates in the caudate-putamen and SNpc. Clearance of these aggregates was region- and cell type-specific, with the early appearance of reactive astrocytes coinciding with accumulation of p129 in the SNpc. Phagocytic microglial cells containing p129 aggregates were observed proximal to p129+ DAn in the SNpc. The majority of neuronal loss in the SNpc occurred during the two-week period after rotenone exposure, subsequent to the peak of microglia and astrocyte activation, as well as the peak of p129 aggregation. A secondary peak of p129 coincided with neurodegeneration at later timepoints. These data indicate that systemic exposure to rotenone in C57Bl/6 mice causes progressive accumulation and regional spread of p129 aggregates that precede maximal loss of DAn. Thus, activation of glial cells and aggregation of p129 appear to drive neuronal loss following neurotoxic stress imposed by exposure to rotenone.
Access this article: https://doi.org/10.1016/j.nbd.2022.105685
Title: The role of enteric glia in intestinal immunity
Authors: Fränze Progatzky, Vassilis Pachnis
Type: Review Article
●Enteric glial cells (EGCs) are required for maintenance of gut tissue homeostasis.
●GFAP+ EGCs regulate the health of the intestinal epithelial barrier.
●EGCs produce immunoregulatory molecules that regulate tissue repair and host defence.
The nervous system and immune system are important interfaces of the gastrointestinal tract that sense, integrate and respond to environmental stimuli and challenges. Enteric glial cells (EGCs), the non-neuronal cells of the enteric nervous system, were long considered mere bystanders only providing support for their workhorse neuronal neighbours. However, work by many groups has demonstrated that EGCs are important nodes in the intestinal tissue circuitry that regulate gastrointestinal barrier function, immunity, host defence and tissue repair. More recent studies have also begun to uncover the cellular interactions and molecular mechanisms that underpin the important functions of EGCs in intestinal physiology and pathophysiology. Here, we review recent literature investigating the roles of EGCs in intestinal immunity and tissue homeostasis.
Access this article: https://doi.org/10.1016/j.coi.2022.102183