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Apoptosis

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Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects

  • Timothy Hansen
  • Claire Thant
  • Joseph A. WhiteII
  • Rupkatha Banerjee
  • Bhasirie Thuamsang
  • Shermali GunawardenaEmail author
Article

Abstract

High levels of oxidative stress is detected in neurons affected by many neurodegenerative diseases, including huntington’s disease. Many of these diseases also show neuronal cell death and axonal transport defects. While nuclear inclusions/accumulations likely cause cell death, we previously showed that cytoplasmic axonal accumulations can also contribute to neuronal death. However, the cellular mechanisms responsible for activating cell death is unclear. One possibility is that perturbations in normal axonal transport alter the function of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-pathway, a signal transduction pathway that promotes survival/growth in response to extracellular signals. To test this proposal in vivo, we expressed active PI3K in the context of pathogenic huntingtin (HTT-138Q) in Drosophila larval nerves, which show axonal transport defects and neuronal cell death. We found that excess expression of active P13K significantly suppressed HTT-138Q-mediated neuronal cell death, but had no effect on HTT-138Q-mediated axonal transport defects. Expression of active PI3K also rescued Paraquat-mediated cell death. Further, increased levels of pSer9 (inactive) glycogen synthase kinase 3β was seen in HTT-138Q-mediated larval brains, and in dynein loss of function mutants, indicating the modulation of the pro-survival pathway. Intriguingly, proteins in the PI3K/AKT-pathway showed functional interactions with motor proteins. Taken together our observations suggest that proper axonal transport is likely essential for the normal function of the pro-survival PI3K/AKT-signaling pathway and for neuronal survival in vivo. These results have important implications for targeting therapeutics to early insults during neurodegeneration and death.

Keywords

Axonal transport Cell death PI3K Motor proteins Huntingtin Huntington’s disease 

Notes

Acknowledgements

We thank the members of the Gunawardena lab for their constructive discussions. This work was supported by grants from the National Institute of Health (R03 NS084386 and R03 NS092024), and BrightFocus Foundation (A2018509S) to SG. TH was supported by fellowships from the Honors College Academic Enrichment Fund, a Honors College Research Scholarship and a Center for Undergraduate Research and Creative Activities (CURCA) fellowship from SUNY at Buffalo. CT was supported by fellowships from CURCA. JW was supported by a College for Arts and Sciences Dissertation Scholarship and a Marc Diamond Research Fellowship. SG thanks Priyantha Karunaratne for constant support.

Author Contributions

TH, CT and SG conceived the experiments. TH, CT, JW, RB, BT conducted and analyzed the results, TH and SG wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest or competing financial interests.

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Authors and Affiliations

  1. 1.Department of Biological SciencesThe State University of New York at BuffaloBuffaloUS
  2. 2.The State University of New York at BuffaloBuffaloUS

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