RESUMO
Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.
Assuntos
Barreira Hematoencefálica , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons , Doença de Leigh , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/deficiência , Doença de Leigh/genética , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/genéticaRESUMO
Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the CNS when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 knockout mouse model of Leigh syndrome. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month-old knockout mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioural improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 knockout mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.
Assuntos
Complexo I de Transporte de Elétrons/genética , Terapia Genética/métodos , Doença de Leigh/genética , Animais , Encéfalo/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Expressão Gênica/genética , Vetores Genéticos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Neurônios/metabolismo , Estudo de Prova de Conceito , Transdução Genética/métodosRESUMO
We recently showed that intranigral transplantation of embryonic neurons in a mouse model of Parkinson's disease led to anatomical and functional recovery of the nigrostriatal pathway. Here we report, in-vivo electrophysiological characteristics of these grafted neurons 2 months after transplantation. Extracellular activity was mapped within the transplant using microarray electrodes and exploration was done with antidromic and orthodromic striatal stimulation. Grafted neurons expressed spontaneous electrophysiological activity with dopaminergic-like characteristics, and antidromic and orthodromic responses suggest a functional recovery of the nigrostriatal loop.
