Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked

Ast, A.; Roth, L.; Brusendorf, L.; Schindler, F.; Ammar, O.W.M.; Berberich, S.; Edel, J.; Bonsor, M.; Georgii, E.; Hänig, C.; Langnick, C.; Ivanov, A.; Beule, D.; Piraud, M.; Kunz, S.; Popp, O.; Mertins, P.; Petzoldt, A.G.; Wanker, E.E.

Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked

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Item Type:	Preprint
Title:	Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked
Creators Name:	Ast, A., Roth, L., Brusendorf, L., Schindler, F., Ammar, O.W.M., Berberich, S., Edel, J., Bonsor, M., Georgii, E., Hänig, C., Langnick, C., Ivanov, A., Beule, D., Piraud, M., Kunz, S., Popp, O., Mertins, P., Petzoldt, A.G. and Wanker, E.E.
Abstract:	Amyloidogenic mutant huntingtin exon-1 (mHTTex1) protein aggregates with pathogenic polyglutamine (polyQ) tracts are the potential root cause of Huntington’s disease (HD). Here, we assessed the gain-of-function toxicity of mHTTex1 aggregation in neurons of HD transgenic flies. We show that the rate of mHTTex1 aggregation in neurons and early mortality of HD transgenic flies are correlated. We observed sequestration of key synaptic proteins into amyloid-like mHTTex1 aggregates and a concomitant decrease of their transcript levels, suggesting that progressive mHTTex1 aggregate stress in neurons leads to an impairment of synaptic function. Machine learning-based data analysis revealed that the abundance of synaptic proteins such as the vesicular monoamine transporter Vmat in the brain is predictive of fly survival. RNAi knockdown of Vmat-encoding transcripts in neurons with pathogenic amyloid-like HTTex1Q97 aggregates further shortened the lifespan of HD flies, supporting the hypothesis that mHTTex1 aggregation drives impairment of synaptic processes and pathogenesis of HD.
Keywords:	Huntington’s Disease, Aggregation, Pathogenic Mechanism, Neurotransmission, RNA Sequencing, Machine Learning, Animals, Drosophila Melanogaster
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.02.06.636778
Date:	7 February 2025
Official Publication:	https://doi.org/10.1101/2025.02.06.636778

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