If you have any problems related to the accessibility of any content (or if you want to request that a specific publication be accessible), please contact us at email@example.com.
|Thesis Advisor||Dagda, Ruben K.|
|Date of Issue||2016|
|Description||The proper localization of high quality mitochondria to distinct neuronal compartments is critical to maintain the integrity of neurites (dendrites and axons). When mitochondria are worn out or damaged, autophagosomes (AVs) recognize and entrap damaged mitochondria to target them for lysosomal-mediated degradation through a process termed mitophagy. Mutations in the mitochondrial serine/threonine kinase PTEN-induced kinase-1 (PINK1) are associated with familial recessive forms of Parkinson’s Disease. Preliminary data from our lab suggests that loss of PINK1 function is associated with robust dendritic pathology including decreased local Protein Kinase A (PKA) signaling in dendrites, decreased mitochondrial content in dendrites, increased mitochondrial fragmentation, and impaired mitochondrial movement in dendrites of primary cortical neurons. PKA can be targeted to microtubules and to mitochondria by binding to dual specificity A-kinase anchoring protein 1 (D-AKAP1) to promote mitochondrial interconnectivity, decrease autophagy and promote dendrite outgrowth in neurons (Dagda et al, 2011; Dagda et al., 2013; Cherra, Dagda, & Chu, 2010). Therefore, based on these observations, I hypothesize that mitochondrial PKA restores mitochondrial content in dendrites in PINK1-deficient neurons via multiple mechanisms including elevating mitochondrial trafficking, decreasing mitophagy, and promoting mitochondrial fusion. By performing live cell imaging, we observed that PKA/D-AKAP1, not a PKA-binding deficient mutant of D-AKAP1 increases mitochondrial content in dendrites, reverses mitochondrial fragmentation, and partially reverses the loss of dendrites in PINK1-deficient neurons. Mechanistically, we observed that D-AKAP1 slows the trafficking of AVs in dendrites and phosphorylates Miro-2 -a mitochondrial trafficking adaptor and substrate of PINK1- as corroborated by Phos-tag analyses of SH-SY5Y cells that transiently express D-AKAP1 and by LC MS/MS. These data suggest that mitochondrial PKA increases mitochondrial content in dendrites by slowing AV trafficking while concomitantly elevating mitochondrial trafficking. Collectively, our data gives proof of principle for developing anti-PD treatments that can reverse the loss of dendrites by eliciting PKA signaling in dendrites.|
|Title||Parkinson’s Disease: effects of PINK1 and PKA on mitochondrial and autophagosomal trafficking and mitophagy in neuronal connections|
|Degree Level||Honors Thesis|
|Degree Grantor||University of Nevada, Reno|