In Parkinson's disease (PD), not only has macroautophagy been proposed to be a potential therapeutic target, but its dysfunction has also been implicated in disease pathogenesis both indirectly and directly. Macroautophagy (MA) is a lysosome-mediated degradation pathway that first sequesters cytosolic constituents into a transient, multimembranous vesicle known as an autophagosome (AP), and then fuses into the endolysosomal system for degradation. Although classically known to promote bulk degradation in response to starvation, MA also promotes the selective turnover of defined substrates in response to different stressors, such as protein misfolding and mitochondrial damage. These selective MA pathways achieve selectivity using adaptor proteins which scaffold cargo to the core autophagic machinery and the nascent AP membrane. Two selective autophagy pathways have been particularly relevant in PD; aggrephagy, the selective degradation of protein aggregates, and mitophagy, the selective degradation of mitochondria. If selective MA pathways are to be considered in global therapeutic strategies for the treatment of PD, it is essential that we apply these questions to the mammalian brain and models of PD. With this in mind, we will use newly created mouse models and methods to examine and validate mechanistically the relevance of these two pathways on pathogenesis in mouse models of genetics PD. First, building upon our identification of the selectivity adaptor for aggrephagy, we will establish the mechanism by which ?-synuclein oligomers enter aggrephagy and whether affecting its degradation might influence the phenotype, with a special emphasis on axonal pathology, in a series of transgenic models of ?-synuclein. Next, building upon our findings that mitochondrial are by far the most prevalent autophagic cargo in the brain, we will examine the mechanism by which PINK1 and Parkin might exert their function in the brain. First, we will establish if compensatory changes in macroautophagic pathways might be responsible for masking the constitutive loss of PINK1 or Parkin in vivo, then use mouse genetics to establish better the relationship between these two PD genes and selective macroautophagy.
The cellular pathway, macroautophagy, has been implicated to provide potential therapeutic benefit in Parkinson's disease. To identify how, our proposal focuses on two key questions that might establish how selective pathways might impact pathogenesis.