Exploring the role of immune system as a primary driver of pathology in the mitochondrial disease Leigh syndrome
Leigh syndrome is the most common paediatric presentation of genetic mitochondrial disease. Patients are typically born healthy, with signs disease most often appearing within the first few years of life. Leigh syndrome is a particularly devastating clinical presentation of mitochondrial disease, with multi organ system involvement and major metabolic and neurologic sequelae such as lactic acidosis and seizures. The defining feature of Leigh syndrome is the appearance of symmetrically located progressive necrotising lesions in the brainstem, which are the ultimate cause of death. Given that over 110 distinct genes are causally linked to Leigh syndrome, with no clear overarching functional links (apart from localising to the mitochondria), putative gene-specific therapies would impact only small subsets of patients. Accordingly, unraveling the mechanisms involved in disease pathogenesis downstream of mitochondria function appears to be the most promising avenue for therapeutic intervention.
Our laboratory has been studying the mechanisms underlying the pathogenesis of Leigh syndrome with this goal in mind. Our studies have focused on understanding two particularly striking features of the disease: 1) the curious post-natal onset of disease symptoms and 2) the progressive, symmetric, neuroinflammatory lesions which are the defining features of the disease.
In this talk, I will discuss our recent work which demonstrates that Leigh syndrome is an immune-mediated disease, and discuss our ongoing studies aimed at further unraveling the steps that lead to immune activation and recruitment to the brain lesion sites. Most remarkably, we’ve found that Leigh syndrome symptoms in the Ndufs4(-/-) mouse model can be prevented in mice by targeting the immune system, without targeting mitochondrial function. In addition, activated peripheral macrophages drive central nervous system lesions. These data reframe our understanding of how primary defects in mitochondrial function lead to pathology and open new avenues for therapeutic intervention.