Sensory Pathology of preclinical Parkinson's Disease

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic cells, and development of Lewy bodies and neurites in the substantia nigra. Patients with advanced PD exhibit motor dysfunction and treatment is available for this degree of degeneration. However, early symptoms are difficult to detect and there are very few safe and reliable biomarkers that can lead to the diagnosis of PD before it progresses to the more advanced stages. Studies have shown that olfactory and visual dysfunction may be biomarkers in the early stages of PD, due to the aggregation of Lewy bodies and neurites in the primary olfactory centers and other areas of the brain. Genes associated with familial PD have been identified; by inserting the human alpha-synuclein genes A30P and A53T in the mutant Drosophila genome, the fruit fly has proven to be an excellent animal model for PD. Young flies, like early-stage Parkinson's patients, show little to no physical symptoms until much of their brains have been devastated by dying dopaminergic neurons and alpha-synuclein inclusions. The adult-onset of motor dysfunction makes it possible to use these transgenic fruit flies as animal models of the pre-clinical stages of the disease. The use of three well established assays to test the visual and olfactory pathologies of preclinical PD is proposed; the Olfactory Magnetic Tether system (OMT) for olfactory- and visually-mediated sensitivity in flight, the stampeding experiment for sensitivity to optomotor cues, and the olfactory-sensitivity using a "T"-Test.

Introduction: PD is the second-most common neurodegenerative, age-related disease today. The physical symptoms of the disease appear in the more advanced stages, and feature a resting tremor, rigidity, akinesia, and postural instability due to the loss of dopaminergic neurons and development of intracytoplasmic inclusions. Olfactory [2-5] and visual [6], [7] dysfunction has been correlated with early idiopathic PD symptoms, and the use of this biomarker, once established, can help develop new and minimally-invasive methods of early diagnosis [1]. Drosophila melanogastor is an excellent model for Parkinson's disease [10-12]. Not only are the genetics of Drosophila thoroughly studied, but the dopaminergic neurons in the nervous system have been carefully documented. Transgenic fruit flies have been shown to develop and exhibit Parkinsonian motor dysfunction and alpha-synuclein inclusions with striking similarities to human PD pathology [10]. So far, mouse models have shown olfactory deficits before the onset of physical symptoms, but animal models of PD-related olfactory impairment are otherwise lacking [8]. By recapitulating these potential early biomarkers for PD, further research can be directed towards better methods to diagnose and treat PD, and Drosophila models of the disease may prove to be even more robust and reliable of animal models. Experimental results from multiple species of animal models may be a stronger predictor of new drugs that will survive the leap to human patients, a better verifier for new tests to diagnose PD in human patients, and inspirational insight for new ideas based on the parallels in PD pathology [11]. In the proposed experiments, the olfactory- and visually-mediated sensitivity in flight, and the sensitivity to optomotor cues and olfactory attraction in walking will be assessed in flies expressing the human alpha-synuclein genes A30P and A53T, and the wildtype human alpha-synuclein as the control.

Advantages of the Drosophila model: Animal models provide insight into universal features that appear in Parkinson's disease [11].
The advantages of Drosophila models include the following:

Genetic mutations are easy to into Drosophila due to well-characterized genetics of the animal [12]
The short lifespan and rapid aging patterns that mimic age-related neurodegenerative disease allow for quick generation time and genetic analysis (10 times faster than mice) [11]
Fruit flies are easy to maintain and can be utilized in large numbers unlike larger animal models
Olfactory and visual detection accounts for most of the environmental cues of almost every type of motivated fruit fly behavior, and are therefore easy to experiment on without extraneous stimuli
Motor dysfunction in Drosophila is easy to detect under the proposed experimental conditions
The neural circuitry and behavior involved in olfactory and visual processing have been studied and stereotyped [13], [14]
Motor dysfunction of genetically-induced PD is grossly preserved in young flies, allowing for extensive behavioral tests, an ideal feature for preclinical PD models [10]
The human-like selective degeneration of dopaminergic neurons, classic Lewy body and neurite formation, and behavioral deficits may prove to be more accurate pathological parallels than many other animal models [8], [10-12]

Implications: Early detection of Parkinson's disease is crucial in planning for long-term care, and recapitulating the key pathological characteristics of PD will help researchers and doctors better understand the disease and how to address it. Drosophila models have been proven to be surprisingly advantageous models for neurodegenerative disease, and the success of multiple animal models can help bolster and facilitate the ongoing research. By improving our understanding of the parallels between human, mouse, and Drosophila PD pathology, researchers can fine-tune conclusions from drug-testing, doctors can diagnose the disease earlier and with better certainty, and specialists can make further hypotheses on the mechanisms of the underlying neuropathologies of this neurodegenerative disease.

References and Acknowledgements: Special thanks to Dawnis Chow, Darcy Wanger, Annie Yang
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[8] Fleming SM et al:Olfactory deficits in mice overexpressing human wildtype α-synuclein. European Journal of Neuroscience, Vol 28, 247-256, (2008)
[9] Polymeropoulos et al: Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047 (1997)
[10] Feany et al: A Drosophila model of Parkinson's disease. Nature Vol 404 (2000)
[11] Shulman JM et al: From fruit fly to bedside: Translating lessons from Drosophila models of neurodegenerative disease. Current Opinion in Neurology 16:443Ð449 (2003)
[12] Beal MF: Experimental models of Parkinson's disease. Nature Vol 2 MAY pp 325-332 (2001)
[13] Duistermars et al: A Magnetic Tether System to Investigate Visual and Olfactory Mediated Flight Control in Drosophila. JoVE 21 (2008)
[14] Zhu Y et al:Peripheral visual circuits functionally segregate motion and phototaxis behaviors in the fly. Curr Biol Apr 14;19(7):613-9. Epub 2009 Mar 19 (2009)

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