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1.
Cell Rep Med ; 5(9): 101715, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39241772

RESUMEN

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI. Pharmacologically preventing Fis1 from binding its mitochondrial partner, dynamin-related protein 1 (Drp1), for 2 weeks after TBI normalizes the balance of mitochondrial fission/fusion and prevents chronically impaired mitochondrial bioenergetics, oxidative damage, microglial activation and lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, and cognitive impairment. Delaying treatment until 8 months after TBI offers no protection. Thus, time-sensitive inhibition of acutely elevated mitochondrial fission may represent a strategy to protect human TBI patients from chronic neurodegeneration.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Dinaminas , Mitocondrias , Dinámicas Mitocondriales , Proteínas Mitocondriales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Animales , Dinaminas/metabolismo , Dinaminas/genética , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Humanos , Ratones , Mitocondrias/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Estrés Oxidativo , Encéfalo/patología , Encéfalo/metabolismo , Microglía/metabolismo , Microglía/patología , Enfermedad Crónica , Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología
2.
Nucleic Acids Res ; 52(16): e76, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39149908

RESUMEN

Our genome is exposed to a wide variety of DNA-damaging agents. If left unrepaired, this damage can be converted into mutations that promote carcinogenesis or the development of genetically inherited diseases. As a result, researchers and clinicians require tools that can detect DNA damage and mutations with exceptional sensitivity. In this study, we describe a massively parallel sequencing tool termed Mutation And DNA Damage Detection-seq (MADDD-seq) that is capable of detecting O6-methyl guanine lesions and mutations simultaneously, with a single assay. To illustrate the dual capabilities of MADDD-seq, we treated WT and DNA repair deficient yeast cells with the DNA-damaging agent MNNG and tracked DNA lesions and mutations over a 24-h time period. This approach allowed us to identify thousands of DNA adducts and mutations in a single sequencing run and gain deep insight into the kinetics of DNA repair and mutagenesis.


Asunto(s)
Daño del ADN , Reparación del ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Saccharomyces cerevisiae , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Saccharomyces cerevisiae/genética , Reparación del ADN/genética , Análisis de Secuencia de ADN/métodos , Aductos de ADN , Mutagénesis
4.
Cell ; 184(10): 2715-2732.e23, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33852912

RESUMEN

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.


Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/prevención & control , Lesiones Traumáticas del Encéfalo/complicaciones , Neuroprotección , Proteínas tau/metabolismo , Acetilación , Enfermedad de Alzheimer/metabolismo , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Línea Celular , Diflunisal/uso terapéutico , Femenino , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante) , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Salicilatos/uso terapéutico , Sirtuina 1/metabolismo , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Factores de Transcripción p300-CBP/metabolismo , Proteínas tau/sangre
5.
Proc Natl Acad Sci U S A ; 117(44): 27667-27675, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33087571

RESUMEN

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Carbazoles/farmacología , Cognición/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/ultraestructura , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Carbazoles/uso terapéutico , Células Cultivadas , Enfermedad Crónica/tratamiento farmacológico , Cognición/fisiología , Modelos Animales de Enfermedad , Células Endoteliales , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Humanos , Masculino , Ratones , Microscopía Electrónica , Microvasos/citología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Fármacos Neuroprotectores/uso terapéutico , Cultivo Primario de Células , Sobrevivientes
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