Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Autor: Anne Eckert, Martine Schmitt, Jürgen Götz, Amandine Grimm, Imane Lejri, François Hallé, Frédéric Bihel
Přispěvatelé: BIHEL, Frédéric, Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Alzheimer's and Parkinson's Disease LaboratoryBrain and Mind Research, Institute, The University of Sydney, Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel (Unibas), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
medicine.medical_specialty
Cell Survival
Endocrinology
Diabetes and Metabolism
[CHIM.THER] Chemical Sciences/Medicinal Chemistry
Tau protein
030209 endocrinology & metabolism
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Steroid biosynthesis
Mitochondrion
Ligands
bioenergetics
TSPO ligands
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Endocrinology
Receptors
GABA
Cell Line
Tumor
Internal medicine
medicine
Translocator protein
Humans
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
ComputingMilieux_MISCELLANEOUS
pregnenolone
biology
ATP synthase
Endocrine and Autonomic Systems
Chemistry
Original Articles
Alzheimer's disease
medicine.disease
Mitochondria
Cell biology
Tauopathies
biology.protein
Pregnenolone
Original Article
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Tauopathy
Cellular model
Energy Metabolism
030217 neurology & neurosurgery
medicine.drug
Zdroj: Journal of Neuroendocrinology
Journal of Neuroendocrinology, 2019, ⟨10.1111/jne.12796⟩
Journal of Neuroendocrinology, Wiley, 2019, ⟨10.1111/jne.12796⟩
ISSN: 0953-8194
1365-2826
DOI: 10.1111/jne.12796
Popis: Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.
Databáze: OpenAIRE
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