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Involvement of T-complex protein 1- ring complex/chaperonin containing T-complex protein 1 (TRiC/CCT) in retrograde axonal transport through tau phosphorylation
杭州旅游景点攻略The cytosolic chaperonin T-complex protein 1-ring com-plex (TRiC) or chaperonin containing T-complex protein 1 (CCT) is esntial in de novo folding of approximately 10% of the eukaryotic, newly translated polypeptides as well as misfolded proteins. There is a clo link between the TRiC/CCT cytosolic chaperonin and neurodegenerative dias (Lopez et al., 2015). A lot of rearch suggests that CCT plays neuroprotective roles in neurodegenerative dias including Huntington’s dia (Lopez et al., 2015). Either overexpression of a single or all eight subunits (CCT1-8) or treatment of the substrate-binding apical domain of yeast CCT1 (ApiCCT1) prevented mutant Huntingtin aggrega-tion and improved cellular and neuronal functions (Zhao et al., 2016). Importantly, our recent study has demonstrated that both CCT and ApiCCT could reduce mutant Hun-tingtin level and enhance both anterograde and retrograde axonal transport of brain-derived neurotrophic factor. The results led to restoration of the trophic status of striatal neurons from a bacterial artificial chromosome transgenic mou model of Huntington’s dia (Zhao et al., 2016). Axonal transport is regulated by many factors including microtubule-associated protein tau, which promotes tubulin polymerization and stabilizes microtubules. Impaired inter-action between tau and microtubules plays a vital role in the pathogenesis of multiple neurodegenerative dias (Wang and Mandelkow, 2016). Interestingly, tau phosphorylation is also obrved in brains of veral Huntington’s dia mou models and Huntington’s dia patients (Gratuze et al., 2016). In a re驴的成语
巴彦淖尔旅游cent study, we explored if CCT subunit has any effect on axonal transport in a tau-dependent pathway (Chen et al., 2018b). We focud on the retrograde axonal transport of brain-derived neurotrophic factor, as neuro-trophic factor-mediated signaling in the form of signaling endosome is esntial in both the developing and the mature nervous system and dysregulation of trafficking of neuro-trophic factors is tightly linked to disorders of the nervous system (Chen et al., 2018a). We found that the expression of a single CCT subunit (CCT5) significantly promoted retro-grade axonal transport of brain-derived neurotrophic factor in primary cortical neurons. Mechanically, CCT regulated the level of cyclin-dependent kina 5 (CDK5)/p35/p25 and, subquently contributed to CCT-induced tau phosphory-lation, which induced detachment of tau from microtubules (Chen et al., 2018b) (Figure 1).
CCT subunit modulates retrograde axonal transport in a tau-dependent manner: Lentivirus-mediated upregulation of CCT5 in primary cortical neurons resulted in an increa in instantaneous velocity (the absolute velocity calculated from moving time without pau time included) and a de-crea in both the percentage of pau events and average pau duration of retrograde brain-derived neurotrophic factor axonal transport in microfluidic chamber. Con-quently, the average retrograde velocity (the relative velocity calculated from moving time with pau time included) in CCT5-express
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ing neurons was significantly faster than obrved in control neurons. Futhermore, CCT5 overex-pression also incread the percentage of nonpau (motile) puncta. The results clearly indicate CCT5 overexpression promotes retrograde axonal brain-derived neurotrophic fac-tor transport (Chen et al., 2018b). Importantly, by using the cortical neurons from tau –/– mice, in combination with len-tivirus expressing wild-type tau (tau WT ), we have proven that the effect on retrograde axonal transport by CCT subunit requires tau expression. Interestingly, reintroducing tau P301L , a pathogenic tau mutant, into tau –/– primary neurons could not rescue the effect of CCT5 on retrograde axonal trans-port, which highlights the differential regulation of tau WT and tau P301L by CCT subunit (Chen et al., 2018b).
排卵症状套用格式>男生真爱一个人的表现Tau plays an important role in axonal transport of multi-ple cargoes including various vesicles and organelles. How-Figure 1 T-complex protein 1-ring complex (TRiC)/chaperonin containing T-complex protein 1 (CCT) subunit enhances retrograde axonal transport by modulating tau phosphorylation. CCT enhances retrograde axonal transport of brain-derived neuro-trophic factor (BDNF) in primary cortical neurons. The net effect on retrograde axonal transport of BDNF by CCT is the reduction in paus-es with a concomitant increa in transport velocities. Importantly, the effect of CCT subunit on retrograde axonal transport of BDNF required tau expression. Mechanically, upregulation of CCT sub
unit increas the level of cyclin-dependent kina 5 (CDK5)/p35/p25 in a tau-de-pendent manner, resulting in tau phosphorylation, which potentially induced tau detachment from microtubules.
