| Summary: |
Millions of people worldwide are afflicted or at risk to develop neurodegenerative diseases for which there is an unmet need for treatments with disease-modifying potential. To address the challenge of developing such treatments it is crucial to have robust models of neurodegeneration and to validate therapeutic targets. Rare monogenic disorders that present selective neuronal death, such as Huntington's disease (HD), provide singular opportunities to investigate mechanisms of neurodegeneration and test neuroprotective strategies. Polyglutamine expansion mutations in the N-terminal region of huntingtin (Htt) cause HD. Despite its widespread distribution, mutant Htt (mHtt) kills striatal neurons earlier and in higher numbers. The mechanisms behind this striatal vulnerability remain unclear. Still, HD neurodegeneration is intrinsically linked to mHtt and, therefore, treatments that promote mHtt clearance in neurons are posited to have disease-modifying potential. Age-dependent reduction in the neuronal capacity for mHtt clearance accumulates toxic mHtt species that can impair mitochondria and induce an ATP shortage that further reduces mHtt clearance. Mitochondrial damage in HD may arise from the production of reactive oxygen species (ROS) induced by mHtt, suggesting that defending mitochondria from ROS should afford neuroprotection. In this project we will test the hypotheses that promoting mHtt clearance, or preventing mitochondrial oxidative damage, hold disease-modifying potential in HD. We will address open questions concerning the consequences of interfering with protein quality control and clearance mechanisms in neurons; investigate how early mitochondrial dysfunction interacts with mHtt proteostasis; and examine how these interactions might contribute for neuronal dysfunction and differential vulnerability in HD. |