| dc.description.abstract |
Parkinson's disease (PD) is a neurodegenerative disorder that reduces both quality and
length of life. PD is characterized by a resting tremor, rigidity, and akinesia (impaired bodily
movements); these and other symptoms are due to well-studied
abnormalities such as the loss of
dopaminergic (DA) neurons in the midbrain and the presence of inclusions, which in the case of
PD, are aggregations of proteins and other substances in vulnerable cells. However, the
underlying cause of these abnormalities is still a mystery.
A clue to the fundamental changes that lead to PD may lie in the intracellular inclusions,
which are known as Lewy bodies and seem to be primarily composed of a protein called alpha-synuclein.
Mutations in alpha-synuclein
have been linked to several prominent cases of familial
PD (an inherited form of the disease); since alpha-synuclein's
function is unclear, further
exploration may elucidate what role it plays in a healthy individual and how changes in the
protein can lead to PD.
It is very difficult to directly examine what alpha-synuclein
does in human subjects.
Hundreds of PD patients and “healthy” human controls would be necessary for comparison and
to reach statistically sound conclusions. There would be too many variables involved (e.g.
nutrition and other environmental factors) that may obscure any connections that can be drawn
between alpha-synuclein
at the biochemical level and PD at the level of the human body as a
whole. Therefore, many current experimental approaches involve simpler animal models. The
fruit fly Drosophila melanogaster can serve as a fitting model for human PD, because
introduction of the gene for alpha-synuclein
leads to PD-like
symptoms in the insect, including
loss of DA neurons, reduced lifespan, and formation of alpha-synuclein rich
inclusions all
major
characteristics of the human disease.
In my research, I used genetics and biochemical techniques to express (i.e. “turn on”) the
gene for alpha-synuclein
in specific tissues and quantities in fruit flies to look for interesting
phenomena and patterns. I also applied stress to some of these flies in two ways, either in the
form of “wet” starvation (withdrawing food but not water) or by exposing them to paraquat, a
chemical agent known to cause PD in humans.
Different combinations of the experimental factors (the presence/absence of the alpha-synuclein
protein and its mutants, the type of stressor applied, and the sex of the fly) led to
different longevities, or lengths of survival, for the flies. The results show that effectively
modeling PD with alpha-synuclein
transgenic flies requires expression in the right tissues, as
well as the correct form of environmental stress (e.g. oxidation via paraquat). |
