The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein

Angeloni, Elisa; Germelli, Lorenzo; Marchetti, Laura; Pozzo, Eleonora Da; Tremolanti, Chiara; Wetzel, Christian H.; Baglini, Emma; Taliani, Sabrina; Passetti, Federico Da Settimo; Martini, Claudia; Costa, Barbara

doi:10.1016/j.bbadis.2023.166751

Cited by 5 publications

(5 citation statements)

References 73 publications

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“…Similarly, TSPO-knockout murine glioma cells and TSPO-knockdown human microglial cells displayed signi cantly higher cytosolic ROS levels than wild-type cells 57,71 .…”

Section: Mitochondrial Membrane Potential and Ca And Redox Homeostasismentioning

confidence: 95%

“…A more recent study not only con rmed the steroidogenic role of human microglia but also highlighted the explicit involvement of TSPO in this process 34 . Moreover, Angeloni et al also suggested a role of TSPO in cholesterol tra cking and neurosteroid synthesis in human microglia, since TSPO silencing resulted in impaired cholesterol homeostasis, leading to excessive cholesterol accumulation 57 . Lin et al demonstrated the ability of human microglia and astrocytes to produce pregnenolone despite low levels of P450scc mRNA and no detectable protein expression.…”

Section: Role Of Tspo In Neurosteroidogenesismentioning

confidence: 99%

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A comprehensive functional investigation of the human translocator protein 18 kDa (TSPO) in a novel human neuronal cell knockout model: from molecule to depression

Wetzel,

Bader,

Jahner

et al. 2024

Preprint

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The translocator protein 18 kDa (TSPO) is a multifunctional outer mitochondrial membrane protein associated with various aspects of mitochondrial physiology and multiple roles in health and disease. Here, we aimed to analyze the impact of TSPO on the regulation of mitochondrial and cellular function in a human neuronal cell model. We used the CRISPR/Cas9 technology and generated TSPO knockout (KO) and control (CTRL) variants of human induced pluripotent stem cells (hiPSCs). In a multimodal phenotyping approach, we investigated cellular and mitochondrial function in neural progenitor cells (NPCs), astrocytes, and neurons differentiated from hiPSC CTRL and TSPO KO cell lines. Our analysis revealed reduced mitochondrial respiration and glycolysis, altered Ca2+ levels in the cytosol and mitochondrial matrix, a depolarized MMP, and increased levels of reactive oxygen species, as well as a reduced cell size. Notably, TSPO deficiency was accompanied by reduced expression of the voltage-dependent anion channel (VDAC). We also observed a reduced TSPO and VDAC expression in cells derived from patients suffering from major depression (MDD). Considering the modulatory function of TSPO and the similar functional phenotype of cells derived from patients with depression, we discuss a role of TSPO in the aetiology or pathology of MDD. Taken together, these findings indicate the impairment of mitochondrial function in TSPO KO cells, contributing to the understanding of the multifaceted role of TSPO and setting the stage for further investigations to unravel the underlying mechanisms and its involvement in various physiological and pathological processes.

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“…Similarly, TSPO-knockout murine glioma cells and TSPO-knockdown human microglial cells displayed signi cantly higher cytosolic ROS levels than wild-type cells 57,71 .…”

Section: Mitochondrial Membrane Potential and Ca And Redox Homeostasismentioning

confidence: 95%

Section: Role Of Tspo In Neurosteroidogenesismentioning

confidence: 99%

A comprehensive functional investigation of the human translocator protein 18 kDa (TSPO) in a novel human neuronal cell knockout model: from molecule to depression

Wetzel,

Bader,

Jahner

et al. 2024

Preprint

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“…PIGA1138 (15 mg/kg) significantly reduced disease severity, improved motor function, preserved myelin integrity, and prevented axonal damage in the CNS. Additionally, it inhibited immune cell infiltration and promoted anti-inflammatory responses, suggesting its potential in managing PPMS [115,116].…”

Section: Multifunctional Indole-based Compounds As Potential Anti-neu...mentioning

confidence: 99%

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Barresi,

Baglini,

Poggetti

et al. 2024

Molecules

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Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

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“…Finally, compound 12 ( Figure 8 ) was also employed to investigate the impact of neurosteroidogenesis on cholesterol homeostasis in an in vitro human microglia model, with cholesterol accumulation usually being associated with the impairment of neuroinflammatory response, favoring neurodegenerative disease progression. The results evidenced the crucial role played by TSPO ligands, such as 12 , in promoting neurosteroidogenesis, allowing for the restoration of cholesterol homeostasis and thus the maintenance of the correct functionality of microglia for the treatment of brain diseases related to neuroinflammation [ 61 ].…”

Section: Indolylglyoxylamides With Anxiolytic-like and Neuroprotectiv...mentioning

confidence: 99%

“…Indolylglyoxylamides with Antitumoral Properties Cancer is the main cause of death worldwide, accounting for more than 19.3 million newly diagnosed cases. The widely recognized multistep process of carcinogenesis as-Activity Cell Line/Animal Model Reference Immunomodulation Human C20 microglial cells [58] Modulation of inflammatory-based retinal neurodegeneration LPS-induced degeneration in 661W cells [59] Neuroprotection Female mouse model of primary progressive multiple sclerosis [60]Maintenance of the correct functionality of microglia in neuroinflammation Human microglia C20 and HMC3 cells[61]…”

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confidence: 99%

Indol-3-ylglyoxylamide as Privileged Scaffold in Medicinal Chemistry

et al. 2023

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In recent years, indolylglyoxylamide-based derivatives have received much attention due to their application in drug design and discovery, leading to the development of a wide array of compounds that have shown a variety of pharmacological activities. Combining the indole nucleus, already validated as a “privileged structure,” with the glyoxylamide function allowed for an excellent template to be obtained that is suitable to a great number of structural modifications aimed at permitting interaction with specific molecular targets and producing desirable therapeutic effects. The present review provides insight into how medicinal chemists have elegantly exploited the indolylglyoxylamide moiety to obtain potentially useful drugs, with a particular focus on compounds exhibiting activity in in vivo models or reaching clinical trials. All in all, this information provides exciting new perspectives on existing data that can be useful in further design of indolylglyoxylamide-based molecules with interesting pharmacological profiles. The aim of this report is to present an update of collection data dealing with the employment of this moiety in the rational design of compounds that are able to interact with a specific target, referring to the last 20 years.

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The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein

Cited by 5 publications

References 73 publications

A comprehensive functional investigation of the human translocator protein 18 kDa (TSPO) in a novel human neuronal cell knockout model: from molecule to depression

A comprehensive functional investigation of the human translocator protein 18 kDa (TSPO) in a novel human neuronal cell knockout model: from molecule to depression

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Indol-3-ylglyoxylamide as Privileged Scaffold in Medicinal Chemistry

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