Interactions among models of amyotrophic lateral sclerosis and Parkinson disease in Drosophila melanogaster

Hurley, Emily Priscilla (2020) Interactions among models of amyotrophic lateral sclerosis and Parkinson disease in Drosophila melanogaster. Masters thesis, Memorial University of Newfoundland.

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. In contrast, Parkinson Disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons within the substantia nigra region of the brain. Recently, a number of genes have been identified to be involved in the progression of these diseases, this study focuses upon four ALS-related genes: TARDBP(TBPH), p62/SQSTM1(Ref(2)P), TBK1(IK2), and VCP(TER94). These genes have been linked to the autophagy pathway and its sub-type, mitophagy, which have been suggested to play substantial roles in the progression of ALS and PD. Employing the Drosophila model organism, I have investigated the consequences of the altered expression of these ALS-related genes in combination with modified PD gene activities in an attempt to discover potential interactions and similarities between the biological basis of neurodegenerative diseases and aging. Notable observations show that the inhibition of TBPH in the motor neurons leads to a reduction in longevity and locomotor ability, and, in complementary experiments, inhibition of TBPH in the developing neuron-rich Drosophila eye reduces the ommatidia and interommatidial bristle counts. The overexpression of IK2 in the motor neurons reduces longevity and locomotor ability. The inhibition of Ref(2)P in the motor neurons, as well as in the dopaminergic neurons, increases median lifespan, slightly, while severely reducing locomotor ability, which may suggest a compensational relationship between longevity and motor function. The inhibition of Ref(2)P and parkin in the ddc-Gal4-expressing neurons provided an increase in lifespan, while resulting in a reduction in locomotor ability. Investigation of the inhibition of TER94 provided variable results, however I have shown that inhibition of TER94 in the dopaminergic neurons can reduce longevity and locomotor ability over time. The co-inhibition of TER94 and parkin has shown a marked reduction in lifespan (by ~30%) and a reduction in locomotor ability. In contrast, the inhibition of TER94 in combination with the expression of alpha-synuclein has shown an large increase in lifespan (by ~28%), with an accompanying reduction in locomotor ability over time. Investigation of these candidate genes and their role in a model of human disease progression has provided some clues to our understanding of ALS and PD.

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