Mitochondria and autophagy in the context of Parkinson's disease
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Abstract
Parkinson's disease (PD) affects millions of people worldwide and currently no treatments alter the progression of the illness. The most salient feature of PD is neurodegeneration of specific cell types characterized by protein aggregation and mitochondrial dysfunction. Information about mechanisms that interconnect these well-established pathological findings has remained elusive.
Autophagy is a process for sequestration and removal of intracellular debris, such as aggregated proteins and damaged mitochondria. Beyond this vital housekeeping role, autophagy is also an essential component of responses to cellular stress. Progressive loss of autophagy in susceptible neuronal populations represents a unifying theory of PD pathology and this dissertation further elucidates connections between mitochondria, autophagy, and PD.
Mutations in LRRK2 are the most common cause of PD and we tested the effects of LRRK2 in transgenic nematodes. Expression of LRRK2 resulted in protection from mitochondrial toxins yet exacerbated sensitivity to tau toxicity. Co-expression of V337M tau with LRRK2 exacerbated tau-mediated motor deficits, which could be rescued by treatment with an enhancer of autophagic flux, ridaforolimus. Markers of oxidative stress were also increased by coexpression of V337M tau with LRRK2. Proteomics studies suggest LRRK2 alters levels of an essential lysosomal component, V-type ATPase, and an assay of autophagic flux supports this mechanism.
In separate experiments, inhibition of farnesyltransferase (FTI) was sufficient to alter autophagy. The size and direction of FTI effect was dependent on the dose of inhibitor. Doses that increase autophagic flux were protective against a lipotoxicity-based model of autophagic impairment. The effects of FTI on mitochondrial transport and performance in primary hippocampal neurons were also assayed. Using live cell imaging, we determined that mitochondrial motility was increased in hippocampal neurons treated with FTI. Increased transport correlated with enhanced mitochondrial oxygen consumption rates.
Our results strengthen associations between mitochondria, autophagy, and PD. We show that LRRK2 alters sensitivity to mitochondrial and protein toxicity. We also describe novel therapeutic approaches that modulate autophagy and mitochondria, which may be useful for treatment of PD.
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Thesis (Ph.D.)--Boston University
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