Our overarching goal is to define the molecular mechanisms underpinning the pathogenesis of mitochondrial disease. Our overall objective in the studies proposed here, which represent the next step in pursuing this goal, is to characterize the pathogenesis of subacute necrotizing encephalopathy and define the role of mTOR in this disease using the Ndufs4(KO) model. Genetic mitochondrial diseases include an array of symptoms, may affect one organ or present as a multisystem disorder, and are remarkably heterogeneous in severity. There are few good models for these diseases and no effective treatment options for mitochondrial disease of any etiology. A clear understanding of the pathogenesis of individual mitochondrial diseases is severely needed; the molecular mechanisms underlying their multiple distinct clinical manifestations are currently unknown. Subacute necrotizing encephalomyelopathy, or Leigh syndrome (LS), is a fatal pediatric mitochondrial disease. Characteristic features of LS include region specific necrotizing lesions of the brain. Though these lesions are the major defining feature of LS, virtually nothing is known of initiating events, what underlies the spatial and temporal specific aspects of the disease, or why some regions of the CNS are inexplicably spared. Our recent work has shown that inhibition of the nutrient sensing signaling complex mTOR attenuates LS in a mouse model, but the mechanisms underlying the benefit are unknown. The goal of this proposal is to define the pathogenesis of LS and the role of mTOR in this disease. We hypothesize that the neurological lesions characteristic of LS result from region and cell-type specific effects of mitochondrial dysfunction, and that mTOR inhibition acts through a discreet downstream neurotoxic pathway. Our experiments will take advantage of the Ndufs4(KO) mouse model of LS, a premier model of human genetic mitochondrial disease which closely resembles human LS. Using this model, we will use characterize the cellular and molecular pathogenesis of neurological lesions in LS by i) identifying the earliest type of cell death and ii) the CNS cell types first lost in lesion formation, iii) defining the region, cell, and cell compartment specificity of phospho-proteome changes during CNS lesion formation, and iv) testing the role of key mTOR regulated pathways in LS using pharmacological approaches. Ultimately, this work will expose basic molecular features of LS and mitochondrial disease in general. In addition, the career development and training components of this proposal will provide key elements for my successful transition to an independent career.

Public Health Relevance

While genetic mitochondrial diseases share common cell and molecular features, such as increased oxidative stress and reduced mitochondrial respiratory capacity, individual diseases are associated with vastly different clinical presentations ranging from single organ dysfunction to complex multi-system pathologies. A clear description of the molecular pathogenesis of individual mitochondrial disorders and a molecular basis for their distinct clinical manifestations remains elusive. The aim of the studies in this proposal is to characterize the pathogenesis of the neurological lesions characteristic of subacute necrotizing encephalopathy and define the role of the nutrient signaling complex mTOR, which has been shown to significantly modulate these lesions, in the pathogenesis of this disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Anderson, Vernon
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Seattle Children's Hospital
United States
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