Advisory Committee Chair
Kevin A Roth
Advisory Committee Members
Steven L Carroll
John J Shacka
Elizabeth S Sztul
W Anne Theibert
Talene A Yacoubian
Document Type
Dissertation
Date of Award
2011
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Parkinson Disease (PD) is the second most common age-related neurodegenerative disorder and is characterized pathologically by the loss of dopaminergic (DA) neurons in the stubstantia nigra pars compacta (SNpc). Mitochondrial dysfunction, increased oxidative stress, and accumulation of aggregated α-synuclein (α-syn), an intracellular protein involved in synaptic function, are all pathological hallmarks of PD have been implicated in PD pathogenesis. However, it is debated whether α-syn aggregates themselves are responsible for neurodegeneration in PD, cellular pathways involved in degradation of α-syn aggregates are believed to promote neuron survival. The autophagy lysosomal pathway (ALP), a physiological mechanism for recycling of intracellular components, has been shown to clear α-syn, its aggregates, and regulate neuron survival in PD. The first part of this dissertation reviews the developments regarding the contribution of the ALP to neuron survival and death regulation. It discusses the effects of oxidative stress on ALP function and vice versa. The role of the lysosome, a cellular organelle responsible for digestion of intracellular constituents delivered via ALP, in regulation of neuron survival is highlighted. Increased oxidative stress and α-syn aggregate accumulation has been reported in PD models of mitochondrial dysfunction such as that induced by the insecticide rotenone. Another part of this dissertation focused on rotenone's effects on ALP function. Rotenone-induced inhibition of lysosomal function has been observed. Our findings suggested that lysosomal dysfunction may be responsible for α-syn accumulation and neuron death observed in PD, implying that mechanisms improving lysosomal function may be cytoprotective. This hypothesis was tested in the second chapter of this dissertation using a chloroquine (CQ) model of lysosome dysfunction. CQ, a known antimalarial agent, induced α-syn accumulation and neuron death by inhibiting ALP function. Bafilomycin A1, a plecomacrolide antibiotic, attenuated CQ-induced neuron death, an effect accompanied by restoration of lysosomal function. These studies expand our knowledge of the potential role of the ALP in PD pathogenesis and suggest that further studies are needed to both decipher the neuroprotective role of the ALP in preventing neuron death in response to PD-associated stimuli, such as rotenone, and to identify novel ALP-related molecular targets for PD therapy.
Recommended Citation
Pivtoraiko, Violetta N., "Regulation of neuronal death by the autophagy lysosomal pathway: implications for Parkinson disease" (2011). All ETDs from UAB. 2732.
https://digitalcommons.library.uab.edu/etd-collection/2732