1. 4,4'-[(2R*,3R*,4R*,5R*)-3,4-Dimethyl-tetra-hydro-furan-2,5-di-yl]diphenol
Juan Manuel de Jesús Favela-Hernández, María Del Rayo Camacho-Corona, Sylvain Bernès, Marcos Flores-Alamo Acta Crystallogr Sect E Struct Rep Online. 2012 Oct 1;68(Pt 10):o3019-20. doi: 10.1107/S1600536812039359. Epub 2012 Sep 26.
The title mol-ecule, C(18)H(20)O(3), is a furan-oid lignan extracted from the leaves of Larrea tridentata. The relative absolute configuration for the four chiral centers was established, showing that this compound is 4-epi-larreatricin, which has been previously reported in the literature. The mol-ecule displays noncrystallographic C(2) symmetry, with the methyl and phenol substituents alternating above and below the mean plane of the furan ring. The conformation of this ring is described by the pseudorotation phase angle P = 171.3° and the maximum out-of-plane pucker ν(m) = 37.7°. These parameters indicate that the furan ring adopts the same conformation as the ribose residues in B-DNA. The packing is dominated by inter-molecular O-H⋯O hydrogen bonds. The phenol hy-droxy groups form chains in the [110] direction and these chains inter-act via O-H⋯O(furan) contacts.
2. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Meihua Jin, et al. Nat Commun. 2021 Nov 15;12(1):6565. doi: 10.1038/s41467-021-26851-2.
Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
3. Tauopathies: new perspectives and challenges
Yi Zhang, Kai-Min Wu, Liu Yang, Qiang Dong, Jin-Tai Yu Mol Neurodegener. 2022 Apr 7;17(1):28. doi: 10.1186/s13024-022-00533-z.
Background: Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body: Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Conclusions: Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.
