The Role of Dynamin Like Protein 1 in Parkinson's Disease
Hoekstra, Jake Gregor
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Parkinson's disease (PD) is a neurodegenerative disease diagnosed by the presence of various motor symptoms, which result from loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In addition to these motor defects, numerous non-motor symptoms occur and appear prior to the onset of clinical symptoms. Significant information implicates mitochondrial dysfunction in the pathogenesis of PD, with recent evidence showing changes in mitochondrial dynamics may be involved. Although the role of astrocytes has become increasingly recognized as an important factor in promoting neuronal health, their contributions towards PD have yet to be fully realized. This thesis focuses on various aspects related to detection of PD in patients as well as mechanisms of PD that occur through mitochondrial defects, which could represent targets of therapy. Chapter 2 considers the current state of biomarkers in PD and how the development of preclinical markers could be achieved to potentially allow for therapies aimed at preventing neuronal loss. Chapter 3 focuses on mitochondrial involvement in PD and how therapies may act to alleviate mitochondrial deficits. Chapters 4 and 5 examine how astrocytes and excitotoxicity play a role in PD particularly, due to changes in mitochondrial dynamics related to the fission promoting protein dynamin like protein 1 (Dlp1), and how the downstream effects of this could be a target of therapy. Using human tissue and following previous mass spectrometry data, Dlp1 expression was demonstrated to be decreased in the SNpc of PD patients. This decrease occurred in both neurons and astrocytes within the SNpc, a finding that was extended to the same cell types in the frontal cortex of patients without observable cortical degeneration. In pursuing the effects of this decrease in astrocytes, it was observed that knockdown of Dlp1 resulted in extensive interconnection and elongation of mitochondria, combined withan impairment in their movement and localization. Further, knockdown of Dlp1 in astrocytes hindered their ability to protect against the excitotoxic effects of glutamate, which was protected against by blocking NMDA receptors. No changes in expression or localization of the major astrocytic glutamate transporters were observed. Instead, these effects can be tied back to differences in intracellular Ca2+ that occur in response to glutamate, as the intracellular Ca2+ levels were elevated in astrocytes after Dlp1 was knocked down. This was due to impaired mitochondrial buffering of Ca2+ that originates from the extracellular space. These results identify a novel mechanism of mitochondrial dysfunction due to alterations in dynamics, in astrocytes, as a means through which neurodegeneration in PD could develop. Further, the results that Dlp1 is decreased in the cortex prior to the appearance of degeneration indicates that depression of Dlp1 expression is an early event in PD. They also show that targeting excitoxicity could be an effective means of alleviating PD. Such therapies may prove to be effective in preventing neuron loss, if treatment is administered prior to the onset of clinical symptoms, which is dependent upon the development of preclinical biomarkers.
- Pathology