Abstract Abnormalities in temporal and frontal lobes (TL and FL) have been linked to cognition and neuropsychiatric disorders. While structural and functional differences between the brain lobes have been documented in disease, the cellular heterogeneity in FL and TL and its impact to the vulnerability to genetic risk factors for neuropsychiatric disorders is not well studied. We hypothesize that intrinsic cellular-level differences between TL and FL explain the vulnerability of specific cell types to genetic risk factors and psychoactive drugs. To test this, we integrated single-nucleus transcriptome analysis in fresh human FL and TL with data related to genetic susceptibility and gene dysregulation in neuropsychiatric disease, and response to psychoactive drugs. We also investigate how these differences are associated with gene dysregulation in disease brain. Neuronal cell populations were the most vulnerable to psychiatric genetic risk factors, and more specifically parvalbumin interneurons (PVALB neurons). These PVALB-expressed genetic risk factors were mostly upregulated in the TL compared with FL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. We found GRIN2A and HCN1 , implicated in schizophrenia by genome-wide association studies, to be significantly upregulated in PVLAB from the TL and in brain cortex from schizophrenia patients. Our analysis provides comprehensive evidence for PVALB neurons as the most vulnerable cell type that is implicated in several psychiatric disorders. PVALB neurons showed the highest vulnerability to psychoactive drug response, which was 3.6-fold higher than the vulnerability to genetic risk factors. In summary, we show high vulnerability of PVALB neurons that is specific to the temporal lobe, implying that differences between TL and FL greatly influence the cell vulnerability to genetic risk factors as well as the response to psychoactive drugs. These findings offer insights into how regional brain differences affect the cell type vulnerabilities in neuropsychiatric disorders.
Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.
Programmed cell death is an important biological process that plays an indispensable role in traumatic brain injury (TBI). Inhibition of necroptosis, a type of programmed cell death, is pivotal in neuroprotection and in preventing associated inflammatory responses. Our results showed that necroptosis occurred in human brain tissues after TBI. Necroptosis was also induced by controlled cortical impact (CCI) injury in a rat model of TBI and was accompanied by high translocation of high-mobility group box-1 (HMGB1) to the cytoplasm. HMGB1 was then passed through the impaired cell membrane to upregulate the receptor for advanced glycation end-products (RAGE), nuclear factor (NF)-κB, and inflammatory factors such as interleukin-6 (IL-6), interleukin-1 (IL-1β), as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3). Necroptosis was alleviated by necrostatin-1 and melatonin but not Z-VAD (a caspase inhibitor), which is consistent with the characteristic of caspase-independent signaling. This study also demonstrated that tumor necrosis factor, alpha-induced protein 3 (TNFAIP3, also known as A20) was indispensable for regulating and controlling necroptosis and inflammation after CCI. We found that a lack of A20 in a CCI model led to aggressive necroptosis and attenuated the anti-necroptotic effects of necrostatin-1 and melatonin.
Traumatic brain injury (TBI) is a serious healthcare problem in the United States, with more than 400,000 individuals hospitalized each year and an estimated annual cost of $25 billion; thus TBI is an enormous socioeconomic burden and has significant public health relevance. TBI leads to both direct mechanical damage and functional disturbance in mitochondria, which are key mechanisms contributing to neuronal death after TBI. Therefore, prevention of mitochondrial damage and/or removal of dysfunctional mitochondria (mitophagy) are promising therapeutic strategies. Indeed, in the in vitro model of mechanical stretch injury, mitophagy was observed as early as 1 h and continued for 24 h; however, neuronal death did not occur until 6 h after the insult. The delayed emergence of neuronal death suggests a possible window of opportunity for targeted therapies. In the current research, we studied the role of cardiolipin (CL), a unique mitochondria inner membrane phospholipid, in neuronal death induced by TBI. Manipulation of neuronal CL levels by knocking down CL synthase (CLS, the rate limiting enzyme in the synthesis of CL) using siRNA technology produced 15% and 46% decrease in CL content at 72 h and at 96 h, respectively, without alteration in mitochondrial morphology or function and CL molecular speciation. CLS/CL deficiency markedly inhibited both mechanical stretch induced mitophagy and neuronal death. Using a model of direct mitochondrial injury (rotenone, complex I inhibitor), we reported that mitophagy resulted in externalization of CL to the mitochondrial outer membrane in the primary neurons and suggested redistribution of cardiolipin serves as a mitochondrial “eat-me” signal. Using global lipidomics analysis we showed that TBI induced neuronal death was accompanied by oxidative consumption of polyunsaturated CL and accumulation of more than 150 new oxygenated molecular species in CL. By applying the novel brain permeable mitochondria-targeted electron-scavenger-hemigramicidin nitroxide, we fully prevented CL oxygenation in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, and markedly reduced behavioral deficits. Taken together, the results from doctoral work explored the role of CL after TBI that represents a novel target for neuro-drug discovery.
Abstract Progesterone has been shown to have neuroprotective effects in multiple animal models of brain injury, whereas the efficacy and safety in patients with traumatic brain injury (TBI) remains contentious. Here, a total of seven randomized controlled trials (RCTs) with 2492 participants were included to perform this meta-analysis. Compared with placebo, there was no significant decrease to be found in the rate of death or vegetative state for patients with acute TBI (RR = 0.88, 95%CI = 0.70, 1.09, p = 0.24). Furthermore, progesterone was not associated with good recovery in comparison with placebo (RR = 1.00, 95%CI = 0.88, 1.14, p = 0.95). Together, our study suggested that progesterone did not improve outcomes over placebo in the treatment of acute TBI.
Thyroid hormone (TH) plays a crucial role in neurodevelopment, but its function and specific mechanisms remain unclear after traumatic brain injury (TBI). Here we found that treatment with triiodothyronine (T3) ameliorated the progression of neurological deficits in mice subjected to TBI. The data showed that T3 reduced neural death and promoted the elimination of damaged mitochondria via mitophagy. However, T3 did not prevent TBI-induced cell death in phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (Pink1) knockout mice suggesting the involvement of mitophagy. Moreover, we also found that T3 promoted neurogenesis via crosstalk between mature neurons and neural stem cells (NSCs) after TBI. In neuron cultures undergoing oxygen and glucose deprivation (OGD), conditioned neuron culture medium collected after T3 treatment enhanced the in vitro differentiation of NSCs into mature neurons, a process in which mitophagy was required. Taken together, these data suggested that T3 treatment could provide a therapeutic approach for TBI by preventing neuronal death via mitophagy and promoting neurogenesis via neuron-NSC crosstalk.
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