Autophagy is an essential cellular degradative process that has been implicated in the pathogenesis of several neurodegenerative diseases including Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). During autophagy, autophagosomes form around cargo such as mitochondria, and subsequently fuse with lysosomes to acidify and acquire enzymes to degrade internalized cargos. In neurons, constitutive autophagosome biogenesis preferentially occurs at the axon tip, followed by the robust retrograde axonal transport of autophagosomes back to the cell body. The mechanisms regulating both the axonal transport of autophagosomes and the selective degradation of damaged mitochondria have not yet been determined. Here, I report novel roles for huntingtin and optineurin in regulating these dynamics and show that this regulation is disrupted in models of neurodegenerative disease. Using live cell imaging of primary neurons, I demonstrate that huntingtin regulates autophagosome retrograde axonal transport via its interactions with dynein and the motor adaptor protein HAP1 (huntingtin-associated protein 1). Loss of either huntingtin or HAP1 disrupts autophagosome transport. We also find that expression of the polyglutamine expansion in huntingtin (polyQ-htt) which leads to Huntington's disease disrupts autophagosome transport, resulting in reduced autophagosome motility and inefficient cargo degradation. These observations support a model in which robust autophagosome transport is required for efficient lysosomal encounters along the axon; inhibition of this transport prevents efficient degradation of internalized cargos. To further explore the mechanism regulating autophagy, I also examined the dynamics of selective mitochondrial degradation during PINK1 (PTEN-induced putative kinase 1)/parkin-dependent mitophagy. These studies identified optineurin as a novel autophagy receptor for damaged mitochondria. Optineurin is recruited to the outer mitochondrial membrane (OMM) following parkin-mediated ubiquitination of OMM proteins. Optineurin binds to ubiquitinated proteins via its UBAN domain, and subsequently recruits the autophagosome protein LC3 via its LC3 interacting region (LIR). This pathway is disrupted by either loss of optineurin or an ALS-associated E478G mutation in optineurin's ubiquitin binding domain, leading to inefficient mitochondrial degradation. Together, these studies provide new insights into the mechanisms driving autophagy and mitophagy, and further demonstrate that defects in autophagy may contribute to pathogenesis in both Huntington's disease and familial ALS.