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A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye.

ABSTRACT: Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, also results from accumulation of amyloid-beta 42 (A?42) plaques. These A?42 plaques trigger oxidative stress, abnormal signaling, which results in neuronal death by unknown mechanism(s). We misexpress high levels of human A?42 in the differentiating retinal neurons of the Drosophila eye, which results in the Alzheimer's like neuropathology. Using our transgenic model, we tested a soy-derived protein Lunasin (Lun) for a possible role in rescuing neurodegeneration in retinal neurons. Lunasin is known to have anti-cancer effect and reduces stress and inflammation. We show that misexpression of Lunasin by transgenic approach can rescue A?42 mediated neurodegeneration by blocking cell death in retinal neurons, and results in restoration of axonal targeting from retina to brain. Misexpression of Lunasin downregulates the highly conserved cJun-N-terminal Kinase (JNK) signaling pathway. Activation of JNK signaling can prevent neuroprotective role of Lunasin in A?42 mediated neurodegeneration. This neuroprotective function of Lunasin is not dependent on retinal determination gene cascade in the Drosophila eye, and is independent of Wingless (Wg) and Decapentaplegic (Dpp) signaling pathways. Furthermore, Lunasin can significantly reduce mortality rate caused by misexpression of human A?42 in flies. Our studies identified the novel neuroprotective role of Lunasin peptide, a potential therapeutic agent that can ameliorate A?42 mediated neurodegeneration by downregulating JNK signaling.

SUBMITTER: Sarkar A

PROVIDER: S-EPMC6131139 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye.

Sarkar Ankita A Gogia Neha N Glenn Neil N Singh Aditi A Jones Gillian G Powers Nathan N Srivastava Ajay A Kango-Singh Madhuri M Singh Amit A

Scientific reports 20180910 1

Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, also results from accumulation of amyloid-beta 42 (Aβ42) plaques. These Aβ42 plaques trigger oxidative stress, abnormal signaling, which results in neuronal death by unknown mechanism(s). We misexpress high levels of human Aβ42 in the differentiating retinal neurons of the Drosophila eye, which results in the Alzheimer's like neuropathology. Using our transgenic model, we tested a soy-derived protein Lunasin (Lun) for a po ...[more]

PMID: 30202077

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Project description: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.

Dataset Information

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye.

Publications

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye.

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