Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Pan-Neuronal Expression of Human Mutant Huntingtin Protein in Drosophila Impairs Immune Response of Hemocytes

Version 1 : Received: 14 September 2021 / Approved: 16 September 2021 / Online: 16 September 2021 (11:05:34 CEST)

How to cite: Dhankhar, J.; Agrawal, N.; Shrivastava, A. Pan-Neuronal Expression of Human Mutant Huntingtin Protein in Drosophila Impairs Immune Response of Hemocytes . Preprints 2021, 2021090277 (doi: 10.20944/preprints202109.0277.v1). Dhankhar, J.; Agrawal, N.; Shrivastava, A. Pan-Neuronal Expression of Human Mutant Huntingtin Protein in Drosophila Impairs Immune Response of Hemocytes . Preprints 2021, 2021090277 (doi: 10.20944/preprints202109.0277.v1).

Abstract

Huntington’s disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mutant huntingtin (mHTT) is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression ofmHTT exon1 in neurons could induce immune responses and hemocyte function. In the present study, we intended to monitor perturbations in the hemocytes population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. We found that pan-neuronal expression of mHtt significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. We also observed an increased production of reactive oxygen species (ROS) in plasmatocytes at advanced stages of the disease. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at of disease. All the parameters were monitored progressively, targeting the circulation at larvae stage and hematopoietic pockets in adults at different disease stages, and many alterations were documented in the early stage itself. These findings strongly implicate that neuronal expression of mHtt alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo. Based on these findings, we propose that further insight into the mechanisms through which neuronal expression of mHtt might be inflicting the innate immune responses would facilitate therapeutic inventions aimed at amelioration of HD pathology and improving the quality of life of the patients.

Keywords

Huntington’s disease; transgenic Drosophila; immune response; phenoloxidase activity; phagocytosis; reactive oxygen species

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