Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration

Festa, Beatrice Paola; Siddiqi, Farah H.; Jimenez‐Sanchez, Maria; Won, Hyeran; Rob, Matea; Djajadikerta, Alvin; Stamatakou, Eleanna; Rubinsztein, David C.

doi:10.1016/j.neuron.2023.04.006

Cited by 43 publications

(33 citation statements)

References 71 publications

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“…Nevertheless, it is yet to be determined whether there is a bidirectional communication between neuronal cells and microglia that influences the extent of contact-mediated aggregate transfer upon autophagy inhibition. This hypothesis has gained traction from a recent study demonstrating the non-cell autonomous influence of activated microglia in inhibiting neuronal autophagy in Huntington's disease (HD) and tauopathy (53). This is achieved by the secretion of proinflammatory chemokines CCL-3/-4/-5 by microglia, which results in neuronal mTORC1 activation, and consequently autophagy inhibition, via the chemokine receptor CCR5.…”

Section: Discussionmentioning

confidence: 99%

Differential α-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia

Chakraborty,

Samella,

Nonaka

et al. 2024

Preprint

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Tunneling nanotubes (TNTs) represent a major form of intercellular communication, enabling material exchange of different kinds over long distances between the connected cells. Previous investigations have demonstrated the efficient directional transfer of alpha-Synuclein (alpha-Syn) aggregates from neuronal cells to microglia. However, the mechanisms underlying this directional specificity have remained elusive. Here, we investigate the localization, dynamics, and impacts of alpha-Syn aggregates on the lysosome and autophagic pathways in neuronal and microglial cells. Our findings reveal differential localization of aggregates with lysosomes of neuronal and microglial cells alongside a disparity in lysosomal dynamics. Microglia exhibit a high propensity for lysosomal turnover, particularly through lysophagy, while neuronal lysosomes display compromised degradative capacity and impaired autophagic flux. Consequently, aggregates in neuronal cells are less efficiently targeted for degradation. Furthermore, perturbation of autophagy in neuronal cells elevates TNT-mediated aggregate transfer to microglia. Thus, while revealing distinct effects of alpha-Syn aggregates in neuronal and microglial cells, our study identifies dysfunctional autophagy as a pivotal determinant driving the preferential directional transfer of aggregates from neurons to microglia.

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Section: Discussionmentioning

confidence: 99%

Differential α-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia

Chakraborty,

Samella,

Nonaka

et al. 2024

Preprint

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“…ROS are key signaling molecules primarily involved in the regulation and progression of inflammatory disorders . In this respect, the downscaling effect of PtNPs on microglial activation could be relevant, as it was recently reported that the microglia–neuronal axis can induce autophagy dysfunction in neurons through the secretion of chemokines activating the neuronal mTORC pathway. , …”

Section: Discussionmentioning

confidence: 99%

“…71 In this respect, the downscaling effect of PtNPs on microglial activation could be relevant, as it was recently reported that the microglia−neuronal axis can induce autophagy dysfunction in neurons through the secretion of chemokines activating the neuronal mTORC pathway. 72,73 Several factors can contribute to the higher efficacy of the postlesional treatment with PtNPs. In both the preventive and curative protocols, the time interval between the intraocular PtNP injection and the physiological analysis was constant (15 days), while the main difference between the two protocols is the absence or presence of light-induced inflammation at the time of PtNP injection.…”

Section: Discussionmentioning

confidence: 99%

Platinum Nanozymes Counteract Photoreceptor Degeneration and Retina Inflammation in a Light-Damage Model of Age-Related Macular Degeneration

Cupini,

Di Marco,

Boselli

et al. 2023

ACS Nano

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Degeneration of photoreceptors in age-related macular degeneration (AMD) is associated with oxidative stress due to the intense aerobic metabolism of rods and cones that if not properly counterbalanced by endogenous antioxidant mechanisms can precipitate photoreceptor degeneration. In spite of being a priority eye disease for its high incidence in the elderly, no effective treatments for AMD exist. While systemic administration of antioxidants has been unsuccessful in slowing down degeneration, locally administered rare-earth nanoparticles were shown to be effective in preventing retinal photo-oxidative damage. However, because of inherent problems of dispersion in biological media, limited antioxidant power, and short lifetimes, these NPs are still confined to the preclinical stage. Here we propose platinum nanoparticles (PtNPs), potent antioxidant nanozymes, as a therapeutic tool for AMD. PtNPs exhibit high catalytic activity at minimal concentrations and protect primary neurons against oxidative insults and the ensuing apoptosis. We tested the efficacy of intravitreally injected PtNPs in preventing or mitigating light damage produced in dark-reared albino Sprague–Dawley rats by in vivo electroretinography (ERG) and ex vivo retina morphology and electrophysiology. We found that both preventive and postlesional treatments with PtNPs increased the amplitude of ERG responses to light stimuli. Ex vivo recordings demonstrated the selective preservation of ON retinal ganglion cell responses to light stimulation in lesioned retinas treated with PtNPs. PtNPs administered after light damage significantly preserved the number of photoreceptors and inhibited the inflammatory response to degeneration, while the preventive treatment had a milder effect. The data indicate that PtNPs can effectively break the vicious cycle linking oxidative stress, degeneration, and inflammation by exerting antioxidant and anti-inflammatory actions. The increased photoreceptor survival and visual performances in degenerated retinas, together with their high biocompatibility, make PtNPs a potential strategy to cure AMD.

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“…Thus, it shows a good prognosis for several medical illnesses, including Huntington's Disease and dementia. 42 The in vitro affinity of MVC (IC 50 = 6.4 nM), to compete with the binding of gp120 to the CCR5 receptor was observed to be slightly lower than TAK779, with an IC 50 value of 22 nM, for inhibition of HIV-1. 43 However, MVC was observed to be 100 times more potent than TAK779.…”

Section: Ccr5 Antagonistsmentioning

confidence: 93%

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

Azzman,

Gill,

Hassan

et al. 2024

Reviews in Medical Virology

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The discovery of anti‐retroviral (ARV) drugs over the past 36 years has introduced various classes, including nucleoside/nucleotide reverse transcriptase inhibitors, non‐nucleoside reverse transcriptase inhibitors, protease inhibitor, fusion, and integrase strand transfer inhibitors inhibitors. The introduction of combined highly active anti‐retroviral therapies in 1996 was later proven to combat further ARV drug resistance along with enhancing human immunodeficiency virus (HIV) suppression. As though the development of ARV therapies was continuously expanding, the variation of action caused by ARV drugs, along with its current updates, was not comprehensively discussed, particularly for HIV‐1 infection. Thus, a range of HIV‐1 ARV medications is covered in this review, including new developments in ARV therapy based on the drug's mechanism of action, the challenges related to HIV‐1, and the need for combination therapy. Optimistically, this article will consolidate the overall updates of HIV‐1 ARV treatments and conclude the significance of HIV‐1‐related pharmacotherapy research to combat the global threat of HIV infection.

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Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration

Cited by 43 publications

References 71 publications

Differential α-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia

Differential α-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia

Platinum Nanozymes Counteract Photoreceptor Degeneration and Retina Inflammation in a Light-Damage Model of Age-Related Macular Degeneration

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

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