Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.
SUMMARYDynamic adaptations in synaptic plasticity are critical for learning new motor skills and maintaining memory throughout life, which rapidly decline with Parkinson's disease (PD). Plasticity in the motor cortex is important for acquisition and maintenance of novel motor skills, but how the loss of dopamine in PD leads to disrupted structural and functional plasticity in the motor cortex is not well understood. Here, we utilized mouse models of PD and 2-photon imaging to show that dopamine depletion resulted in structural changes in the motor cortex. We further discovered that dopamine D1 and D2 receptor signaling were linked to selectively and distinctly regulating these aberrant changes in structural and functional plasticity. Our findings suggest that both D1 and D2 receptor signaling regulate motor cortex plasticity, and loss of dopamine results in atypical synaptic adaptations that may contribute to the impairment of motor performance and motor memory observed in PD.
PHOSPHATE STARVATION RESPONSE1 (PHR1) is a key regulatory component of the response to phosphate (Pi) starvation. However, the regulation of in this response remains poorly understood. Here, we report that is a target of the transcription factors AUXIN RESPONSE FACTOR7 (ARF7) and ARF19 and is positively regulated by auxin signaling in Arabidopsis () roots. expression was induced by exogenous auxin and suppressed by auxin transport inhibitors in Arabidopsis roots. In the promoter, three auxin-response elements, which are bound directly by ARF7 and ARF19, were shown to be essential for expression. The, , and mutants showed down-regulated expression of and downstream Pi starvation-induced genes in roots; they also exhibited defective Pi uptake in roots and overaccumulation of anthocyanin in shoots. The induction of lateral root formation in response to low Pi and to exogenous auxin was decreased in the mutant, whereas the expression of () and was not changed significantly. PHR1 acted independently of LBD16 and LBD29 in the regulation of lateral root formation in response to low Pi. Under low-Pi conditions, lateral root impairment in the mutant was partially rescued by constitutive expression of , demonstrating that reduced expression contributed to the phenotype. In addition to, other genes encoding MYB-CC members also were targets of ARF7 and ARF19. Our work thus reveals a mechanism coordinating auxin signaling and the PHR1 regulon in Arabidopsis responses to Pi deficiency.
More than 15 million out of 70 million patients worldwide do not respond to available antiepilepticus drugs (AEDs). With the emergence of nanomedicine, nanomaterials are increasingly being used to treat many diseases. Here, we report that tetrahedral framework nucleic acid (tFNA), an assembled nucleic acid nanoparticle, showed an excellent ability to the cross blood-brain barrier (BBB) to inhibit M1 microglial activation and A1 reactive astrogliosis in the hippocampus of mice after status epilepticus. Furthermore, tFNA inhibited the downregulation of glutamine synthetase by alleviating oxidative stress in reactive astrocytes and subsequently reduced glutamate accumulation and glutamate-mediated neuronal hyperexcitability. Meanwhile, tFNA promotes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization in the postsynaptic membrane by regulating AMPAR endocytosis, which contributed to reduced calcium influx and ultimately reduced hyperexcitability and spontaneous epilepticus spike frequencies. These findings demonstrated tFNA as a potential AED and that nucleic acid material may be a new direction for the treatment of epilepsy.
Phosphorus (P) is one of the essential nutrient elements for plant development. In this work, BnPht1;4 gene, encoding a phosphate transporter of PHT1 family, was isolated from Brassica napus. BnPht1;4 possesses the major characteristic of PHT1 high-affinity Pi transporters in plants, such as plasma-membrane localization and 12 transmembrane-spanning domains. Quantitative reverse-transcription PCR analysis and promoter activity assay showed BnPht1;4 was inert in plants under Pi sufficient conditions. However, expression of this gene was remarkably enhanced in roots under Pi deficient conditions. Interestingly, under low Pi conditions, its promoter activity is impaired in tips of elongated roots, suggesting that the high-affinity Pi transporter may be not involved in low Pi response at root tip area. The experimental results also indicated that BnPht1;4 induction by Pi deficiency is dependent on the existence of sugar. In 35S:BnPht1;4 transgenic Arabidopsis, the increase of Pi availability resulted in the change of root architecture under Pi deficient conditions, showing longer primary roots and lower lateral root density than that of wild type. By cis-element analysis, two P1BS and two W-box elements were found in BnPht1;4 promoter. Yeast one-hybrid assay indicated that PHR1 could bind to the BnPht1;4 promoter. P1BS elements in BnPht1;4 promoter are essential for BnPht1;4 induction in Pi starvation response. Furthermore, WRKY75 could bind to the BnPht1;4 promoter, in which W-box elements are important for this binding. These results indicated BnPht1;4 may be dually controlled by two family regulators under low Pi responses. Thus, our data on the regulative mechanism of high-affinity Pi transporter in Pi starvation response will be valuable for B. napus molecular agriculture.
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