Determination of the Sub-cellular Mechanisms Underlying Neurodegeneration in Parkinson's Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.8% of the population over 65 years of age. It is characterized by three cardinal symptoms: bradykinesia, muscle rigidity and resting tremor. Symptoms are presented following 50% loss of dopaminergic neurons within the substantia nigra pars compacta (SNc). Neurodegeneration is associated with reactive oxygen species (ROS) production, protein aggregation, mitochondrial dysfunction, ubiquitin-proteasome system (UPS) inhibition and lysosomal malfunction; however it is unclear if a single mechanism or multiple mechanisms lead to disease onset. The primary aim of the studies described in this thesis was to elucidate the interactions between various pathological mechanisms underlying PD pathology. An examination of organelle function during exposure of SH-SY5Y neuroblastoma to a variety of toxins which mimic purported pathological processes in PD reveal mitochondrial membrane potential becomes depolarized, not only following mitochondrial impairment, but also after the UPS and lysosome are inhibited. Given that mitochondrial dysfunction appeared to be central to PD pathology, mitochondrial dysfunction was studied in more detail. Mitochondrial fission and fusion maintains mitochondrial integrity, which is critical to neuronal health. Thus, we examined mitochondrial dynamics in a common genetic variant linked with familial PD, known as leucine-rich repeat kinase 2 (LRRK2). Upon the expression of wild-type and mutant LRRK2, mitochondrial fusion was inhibited causing fragmentation of mitochondria. This inhibition of fusion may be the initial step leading to mitochondrial dysfunction, since inhibition of fusion occurs prior to the induction of cell stress. The findings that mitochondrial dysfunction appears to be central to PD pathology, suggest that mitochondria may be an excellent therapeutic target for PD. Thus, the potential neuroprotective function of a regulator of mitochondrial function, known as SIRT3 was examined. In SH-SY5Y cells, over-expression of SIRT3 protected neurons from degeneration associated with LRRK2 over-expression. The studies described in this thesis provide evidence that multiple sub-cellular mechanisms converge to inhibit mitochondrial function. Furthermore, mitochondrial dynamics which regulate mitochondrial function could be a key mediator in the pathology associated with PD. The work herein suggests therapies which target the mitochondria are likely to be successful in the treatment of PD.

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