Homeotic Gene teashirt (tsh) Has a Neuroprotective Function in Amyloid-Beta 42 Mediated Neurodegeneration

Abstract

BackgroundAlzheimer'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/ Principle FindingsWe 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/SignificanceWe 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.

A fruitful endeavor: Modeling ALS in the fruit fly

“…Drosophila has been a useful model organism for performing genetic screens to identify genes and pathways that modify phenotypes associated with neurodegenerative diseases, including spinocerebellar ataxia (Fernandez-Funez et al, 2000;Ren et al, 2011;Shieh and Bonini, 2011), Wolfram syndrome (Jones et al, 2014), Alzheimer’s disease (Moran et al, 2013;Shulman and Feany, 2003) and Huntington’s disease (Kazemi-Esfarjani and Benzer, 2000). Screens can be targeted, testing the effects of an array of known genes on a particular phenotype (Jones et al, 2014;Ren et al, 2011), or they can be unbiased, looking for any genes that modify a phenotype.…”

“…Drosophila at any stage of development can be used, depending on the phenotype of interest (Batlevi et al, 2010;Rorth et al, 1998). Eye degeneration is a commonly used phenotypic output (Kazemi-Esfarjani and Benzer, 2000;Moran et al, 2013), although genetic screens have also been performed using survival (Li et al, 2014), wing posture (Shieh and Bonini, 2011), climbing (Shieh and Bonini, 2011) defects and axonal and synaptic degeneration (Wishart et al, 2012). Here we highlight the genes that have been identified as modifiers of TDP-43-associated neurodegeneration in Drosophila models of ALS.…”

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

“…Several animal AD models have shown promise; however, our Drosophila model allows us to test other signaling pathways using genetic epistasis approaches (Pandey and Nichols, 2011;Lenz et al, 2013;Sabbagh et al, 2013;Sarkar et al, 2016;Deshpande et al, 2019). We previously reported the neuroprotective effects of the apical basal polarity gene crumbs (crb) (Moran et al, 2013;Steffensmeier et al, 2013) and the homeotic gene teashirt (tsh) (Moran et al, 2013) in Aβ42-mediated neurodegeneration. Interestingly, these genetic modifiers are members of the Hippo signaling pathway.…”

“…We previously reported the neuroprotective effects of the apical basal polarity gene crumbs (crb) (Moran et al, 2013;Steffensmeier et al, 2013) and the homeotic gene teashirt (tsh) (Moran et al, 2013), both members of the Hippo signaling pathway. However, the neuroprotective function of Hippo or JNK signaling interactions together has not been fully understood.…”

“…As per the amyloid hypothesis, the accumulation of the Aβ42 peptides into plaques initiates a pathological cascade eventually leading to neurodegeneration (Tare et al, 2011;Selkoe and Hardy, 2016;Yeates et al, 2019). Since this hypothesis was postulated, several signaling pathways and genetic modifiers have been implicated in Aβ42-mediated neurodegeneration (Moran et al, 2013;Steffensmeier et al, 2013;Cutler et al, 2015;Yeates et al, 2019).…”