Document Type
Article
Publication Date
11-2013
Publication Source
PLOS One
Abstract
Background: Alzheimer's disease (AD) is a debilitating age related progressive neurodegenerative disorder characterized by the loss of cognition, and eventual death of the affected individual. One of the major causes of AD is the accumulation of Amyloid-beta 42 (Aβ42) polypeptides formed by the improper cleavage of amyloid precursor protein (APP) in the brain. These plaques disrupt normal cellular processes through oxidative stress and aberrant signaling resulting in the loss of synaptic activity and death of the neurons. However, the detailed genetic mechanism(s) responsible for this neurodegeneration still remain elusive.
Methodology/Principal Findings: We have generated a transgenic Drosophila eye model where high levels of human Aβ42 is misexpressed in the differentiating photoreceptor neurons of the developing eye, which phenocopy Alzheimer's like neuropathology in the neural retina. We have utilized this model for a gain of function screen using members of various signaling pathways involved in the development of the fly eye to identify downstream targets or modifiers of Aβ42 mediated neurodegeneration. We have identified the homeotic gene teashirt (tsh) as a suppressor of the Aβ42 mediated neurodegenerative phenotype. Targeted misexpression of tsh with Aβ42 in the differentiating retina can significantly rescue neurodegeneration by blocking cell death. We found that Tsh protein is absent/ downregulated in the neural retina at this stage. The structure function analysis revealed that the PLDLS domain of Tsh acts as an inhibitor of the neuroprotective function of tsh in the Drosophila eye model. Lastly, we found that the tsh paralog, tiptop (tio) can also rescue Aβ42 mediated neurodegeneration.
Conclusions/Significance: We have identified tsh and tio as new genetic modifiers of Aβ42 mediated neurodegeneration. Our studies demonstrate a novel neuroprotective function of tsh and its paralog tio in Aβ42 mediated neurodegeneration. The neuroprotective function of tsh is independent of its role in retinal determination.
ISBN/ISSN
1932-6203
Document Version
Published Version
Copyright
Copyright © 2013 Moran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher
PLOS One
Volume
8
Peer Reviewed
yes
Issue
11
eCommons Citation
Moran, Michael T.; Tare, Meghana; Kango-Singh, Madhuri; and Singh, Amit, "Homeotic Gene Teashirt (tsh) Has a Neuroprotective Function in Amyloid-Beta 42 Mediated Neurodegeneration" (2013). Biology Faculty Publications. 117.
https://ecommons.udayton.edu/bio_fac_pub/117
Included in
Biology Commons, Computational Biology Commons, Genetics Commons, Genomics Commons, Molecular Biology Commons, Molecular Genetics Commons, Other Genetics and Genomics Commons
Comments
Funding: This work was supported by National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.