Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease

Chouhan, AK, Guo, C, Hsieh, Y-C, Ye, H, Senturk, M, Zuo, Z, Li, Y, Chatterjee, S ORCID: https://orcid.org/0000-0002-2506-1278, Botas, J, Jackson, GR, Bellen, HJ and Shulman, JM, 2016. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease. Acta Neuropathologica Communications, 4 (1): 62.

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Abstract

Common neurodegenerative proteinopathies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system.

Item Type:	Journal article
Publication Title:	Acta Neuropathologica Communications
Creators:	Chouhan, A.K., Guo, C., Hsieh, Y.-C., Ye, H., Senturk, M., Zuo, Z., Li, Y., Chatterjee, S., Botas, J., Jackson, G.R., Bellen, H.J. and Shulman, J.M.
Publisher:	Springer Science and Business Media LLC
Date:	December 2016
Volume:	4
Number:	1
Identifiers:	Number Type 10.1186/s40478-016-0333-4 DOI 1394985 Other
Rights:	© 2016 The Author(s). Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	17 Dec 2020 11:19
Last Modified:	31 May 2021 15:09
URI:	https://irep.ntu.ac.uk/id/eprint/41890

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