Homeotic Gene teashirt (tsh) has a neuroprotective function in amyloid-beta 42 mediated neurodegeneration.

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 (A?42) 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 FINDINGS: We have generated a transgenic Drosophila eye model where high levels of human A?42 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 A?42 mediated neurodegeneration. We have identified the homeotic gene teashirt (tsh) as a suppressor of the A?42 mediated neurodegenerative phenotype. Targeted misexpression of tsh with A?42 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 A?42 mediated neurodegeneration. CONCLUSIONS/SIGNIFICANCE: We have identified tsh and tio as new genetic modifiers of A?42 mediated neurodegeneration. Our studies demonstrate a novel neuroprotective function of tsh and its paralog tio in A?42 mediated neurodegeneration. The neuroprotective function of tsh is independent of its role in retinal determination.

SUBMITTER: Moran MT 

PROVIDER: S-EPMC3840013 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature