Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

Gong, Jing; Szegő, Éva M.; Leonov, Andrei; Benito, Eva; Becker, Stefan; Fischer, André; Zweckstetter, Markus; Outeiro, Tiago F.; Schneider, Anja

doi:10.1523/jneurosci.2070-18.2019

Cited by 51 publications

(44 citation statements)

References 104 publications

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“…18 Reduction of neurons in SNc which project to CPu reflects the nigrostriatal system neurodegeneration after MPTP treatment, suggesting the mouse model of PD was successful ( Figure 5B and D). Consistent with the previous studies, 15 after five days of MPTP injection, a 56% loss of dopaminergic cell bodies in the SNc was observed. 22 The reduction in the number of retrogradely labelled SNc neurons further confirmed MPTP-induced neurodegeneration.…”

Section: Discussionsupporting

confidence: 92%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

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Section: Discussionsupporting

confidence: 92%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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“…These findings were accompanied by prevention of retinal degeneration after injury, hence drastically inhibiting the progression of disease [109]. XBD173 has also been shown to decrease pro-inflammatory cytokines and delay Multiple Sclerosis progression and symptoms in an experimental autoimmune encephalomyelitis (EAE) mouse model [110], and also demonstrated efficacy in attenuating microglial activation and neuronal loss in an MPTP Parkinson's disease model [111].…”

Section: In Vivo Immunomodulation Of Tspo Ligandsmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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“…Previously mentioned evidence about the protective activity of TSPO ligands in CNS disorders has initiated investigations about their effects concerning neurodegeneration. On this account, a study by Gong et al showed that Emapunil, a novel synthetic TSPO ligand, significantly reduced dopaminergic loss in mice with induced PD by inhibiting the unfolded protein response and subsequently reducing cellular stress and apoptosis [65]. Additionally, the authors concluded that the neuroprotective effect of Emapunil might be associated with the partial alteration of neurosteroid levels, which can counteract neuroinflammatory responses [65].…”

Section: Tspo and Parkinson Disease (Pd)mentioning

confidence: 99%

“…On this account, a study by Gong et al showed that Emapunil, a novel synthetic TSPO ligand, significantly reduced dopaminergic loss in mice with induced PD by inhibiting the unfolded protein response and subsequently reducing cellular stress and apoptosis [65]. Additionally, the authors concluded that the neuroprotective effect of Emapunil might be associated with the partial alteration of neurosteroid levels, which can counteract neuroinflammatory responses [65]. Together with other studies applying TSPO ligands for the treatment of brain damage, this investigation showed promising results about exploiting TSPO as a possible therapeutic target for α-synucleinopathies [28,66].…”

Section: Tspo and Parkinson Disease (Pd)mentioning

confidence: 99%

“…Furthermore, radioligand-labeled research revealed the protective effects of moderate-affinity TSPO ligands, such as Etifoxine, against brain injury and brain disorders [168,169]. Thus, TSPO has become the target of research into high-affinity as well as low-affinity therapeutic ligands against various pathologies of the CNS, leading to a plethora of patents [14,65,170,171]. Interestingly, although counterintuitive, from the results of various studies, it can be assumed that low-and moderate-affinity TSPO ligands are at least as efficacious as high-affinity ligands, while showing far fewer risks of side effects [28,47,66,172,173].…”

Section: Tspo and Traumatic Brain Injuries (Tbis)mentioning

confidence: 99%

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Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.

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Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

Cited by 51 publications

References 104 publications

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

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