Htt is a repressor of Abl activity required for APP-induced axonal growth

Abstract

Huntington’s disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer’s disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.

Respective contribution of Appl to mushroom body axon growth and long-term memory inDrosophila

“…Although 9% of Appl C2 . 1 MBs lacked the β lobe, slightly lower than the 14.5% described for Appl d [15], Appl C1 . 4 MBs displayed a much higher penetrance (66%) of this phenotype (Fig 1).…”

Screening for Differentially Expressed Memory Genes on a Diabetes Model Induced by High-Sugar Diet in Drosophila melanogaster: Potential Markers for Memory Deficits

“…3i). In addition to its role in neurodegeneration, Abl is involved in the formation of αβ and α'β' lobes in the mushroom bodies (MB): dysregulation of Abl levels by either overexpression or lack of expression causes disorganization of actin structures and compromises the axonal growth [41]. In line with this, we found previously from this transcriptome a remarkable down-regulation for Actin (Act88F) in HSD ies [19], effect that was associated with a decrease in muscle mass, but that now, as shown here, seems to impact on the correct formation of the nervous system as well.…”

Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition

“…For example, the genes htt and iab-8 (also known as Abd-B ) were associated with variation in climbing speed in both the young control and Lisinopril treatments. htt ( huntingtin ), the Drosophila ortholog of the huntingtin gene (HTT) in humans, has been used as a model in the study of Huntington’s [ 34 ] and Parkinson’s disease [ 35 ] and is important for maintaining mobility in adult flies [ 36 ]. Abd-B has been implicated in muscle development [ 37 ].…”