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Measuring Glucose Uptake in Drosophila Models of TDP-43 Proteinopathy
Published on: August 3, 2021
A Drosophila model for TDP-43 proteinopathy
Yan Li1, Payal Ray, Elizabeth J Rao
1Department of Neurology, Lurie Cancer Center, Center for Genetic Medicine, Northwestern University School of Medicine, Chicago, IL 60611, USA. l-yan@northwestern.edu
Summary
Increased expression of human TAR DNA binding protein-43 (hTDP-43) causes neurotoxicity and neurodegeneration in flies. This finding suggests that aberrant regulation of hTDP-43 contributes to TDP-43 proteinopathies like ALS and FTLD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- TDP-43 proteinopathy, characterized by neuropathology involving TAR DNA binding protein-43 (TDP-43), is implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD).
- The precise mechanisms driving TDP-43 proteinopathy pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate whether elevated expression of wild-type human TDP-43 (hTDP-43) can induce neurotoxicity in vivo.
- To establish a relevant animal model for studying TDP-43 proteinopathies.
Main Methods:
- Generation of transgenic flies expressing wild-type human TDP-43 (hTDP-43) in specific neuronal populations, including eye, mushroom bodies, and motor neurons.
- Assessment of neurodegenerative phenotypes, including ommatidia loss, axon degeneration, neuronal death, and functional deficits.
Main Results:
- Expression of full-length hTDP-43 in fly eyes led to progressive ommatidia loss and neurodegeneration.
- hTDP-43 expression in mushroom bodies resulted in significant axon loss and neuronal death.
- Motor neuron-specific hTDP-43 expression caused axon pathology, motor neuron loss, and functional impairments.
Conclusions:
- Increased expression of hTDP-43 is sufficient to cause neurotoxicity and recapitulates key features of human TDP-43 proteinopathy.
- Aberrant regulation of hTDP-43 expression or impaired clearance may contribute to the pathogenesis of these devastating neurodegenerative diseases.
- Transgenic flies expressing hTDP-43 serve as a valuable model for investigating TDP-43 proteinopathies and developing therapeutic strategies.
