Expression of Human Mutant Huntingtin Protein in Drosophila Hemocytes Impairs Immune Responses

Abstract

The pathogenic effect of mutant HTT (mHTT) which causes Huntington disease (HD) are not restricted to nervous system. Such phenotypes include aberrant immune responses observed in the HD models. However, it is still unclear how this immune dysregulation influences the innate immune response against pathogenic infection. In the present study, we used transgenic Drosophila melanogaster expressing mutant HTT protein (mHTT) with hemocyte-specific drivers and examined the immune responses and hemocyte function. We found that mHTT expression in the hemocytes did not affect fly viability, but the numbers of circulating hemocytes were significantly decreased. Consequently, we observed that the expression of mHTT in the hemocytes compromised the immune responses including clot formation and encapsulation which lead to the increased susceptibility to entomopathogenic nematode and parasitoid wasp infections. In addition, mHTT expression in Drosophila macrophage-like S2 cells in vitro reduced ATP levels, phagocytic activity and the induction of antimicrobial peptides. Further effects observed in mHTT-expressing cells included the altered production of cytokines and activation of JAK/STAT signaling. The present study shows that the expression of mHTT in Drosophila hemocytes causes deficient cellular and humoral immune responses against invading pathogens. Our findings provide the insight into the pathogenic effects of mHTT in the immune cells.

Adenosine receptor and its downstream targets, mod(mdg4) and Hsp70, work as a signaling pathway modulating cytotoxic damage inDrosophila

“…The present study examined the role of Drosophila Ado signaling on cytotoxic stress and aimed to elicit the underlying mechanism. Earlier reports have shown that expression of the expanded polyglutamine domain from human mutant huntingtin protein (mHTT) induces cell death in both Drosophila neurons and hemocytes (Marsh et al, 2000;Lin et al, 2019). In our study, we confirmed the low-viability phenotype of mHTTexpressing larvae and observed that such larvae display a lower level of e-Ado in the hemolymph.…”

Regulatory Roles of Antimicrobial Peptides in the Nervous System: Implications for Neuronal Aging

“…In a Drosophila model of the neurodegenerative disease ataxia-telangiectasia, ataxiatelangiectasia mutated (ATM) kinase results in increased AMP gene expression in glial cells, specifically through the NF-κB pathway (Petersen et al, 2012(Petersen et al, , 2013. Also, Drosophila carrying the mutant form of huntingtin, had impaired expression of a few AMPs, including DptB, Attacin, and cecropin A (Table 1), following bacterial infection (Lin et al, 2019), further suggesting a delicate interrelationship between the innate immune system and some of the key proteins in neurodegenerative diseases. The correlative and common elements between AMPs and neurodegenerative diseases warrants further investigation into whether AMPs are the drivers of the diseases, or misregulated as a consequence of the progression of diseases.…”

Mutation in Drosophila concentrative nucleoside transporter 1 alters spermatid maturation and mating behavior

“…The RT-qPCR was performed as previously described (Lin et al, 2019). Total RNA was extracted from adult flies using TRIzol reagent (#1559026, Invitrogen, USA).…”