Project Details
Projekt
Understanding the molecular pathogenesis of Leigh syndrome and its reversal by hypoxia
Applicant
Dr. Maria del Pilar Miranda Vergara
Subject Area
Molecular and Cellular Neurology and Neuropathology
Cell Biology
Cell Biology
Term
from 2019 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 431313887
Mitochondrial dysfunction is associated to a broad spectrum of human diseases ranging from severe inherited mitochondrial disorders to common neurodegenerative diseases like Parkinson or Alzheimer. Leigh syndrome, the most common pediatric manifestation of mitochondrial disease, is a fatal subacute encephalopathy for which there are no effective therapies to date. Hypoxia has recently emerged as a promising treatment strategy as it prevents and reverses the neurologic phenotype in a murine model of Leigh syndrome (Ndufs4 knockout mouse). However, despite first being described more than six decades ago, the molecular mechanisms underlying Leigh syndrome are not known and a full molecular understanding of the rescue by hypoxia is still missing. Therefore, the overarching goal of this proposal is to elucidate the pathological basis of Leigh syndrome and the rescue mechanisms of hypoxia using novel approaches in mouse genetics, genomics and molecular biology in the Ndufs4 knockout mouse. To achieve this, first we will define the bioenergetic and redox basis of Leigh syndrome and its reversal by hypoxia. Second, we will define the effector cell types and gene expression programs through the progression of Leigh syndrome and their regulation by hypoxia. Third, we will define the contribution of neuroinflammation to the pathogenesis of Leigh syndrome. Successful completion of this proposal will provide molecular insights into the basis of neurodegeneration in a monogenic form of mitochondrial disease and the principles we discover here may be applicable to understand more common forms of neurodegeneration.
DFG Programme
Research Fellowships
International Connection
USA
