A Drosophila Model to Investigate the Role of TDP-43 in Neurodegenerative Diseases and Its Therapeutic Application
Date Issued
2015
Date
2015
Author(s)
Cheng, Ching-Wei
Abstract
TDP-43 is a multi-functional RNA/DNA-binding protein well-conserved among many species including mammals and Drosophila. However, it is also a major component of the pathological inclusions associated with degenerating motor neurons of amyotrophic lateral sclerosis (ALS-TDP). Further, TDP-43 is a signature protein in one subtype of frontotemporal degeneration, FTLD-TDP. Unfortunately, there are no effective drugs for these neurodegenerative diseases. In this thesis, fly models are generated to explore the function and dysfunction of TDP-43. By both down- and up-regulation of the levels of Drosophila ortholog of TDP-43, dTDP, ubiquitously or in specific cell types/ tissues, the important role of the dTDP protein and by implication the mammalian TDP-43 protein as well, in development and in neuronal functioning are examined. For the latter in particular, I show that dTDP regulates learning ability and locomotion of the fruit flies. As a model of the TDP-43 proteinopathies, flies with overexpression of dTDP, either in the mushroom body, in motor neurons, or in PDF (+) neurons, also exhibit dose-dependent and/or age-dependent pathogenesis behavior. Next, I establish a fly model of ALS-TDP with transgenic expression of dTDP in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. These ALS-TDP flies also exhibit diminished lifespan as well as locomotor defects following induction of dTDP. Dissection of the T1/T2 region of the thoracic ganglia has revealed loss of the neurons and the formation of dTDP (+) aggregates. Since the ALS-TDP flies exhibit diseased phenotypes, I utilize this model to examine the therapeutic effect of rapamycin, a TOR-dependent autophagy activator. Although harmful to the control flies, administration of 400
Subjects
TDP-43
amyotrophic lateral sclerosis
frontotemporal lobar degeneration
Drosophila
lifespan
locomotor activity
mushroom body
Type
thesis
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