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Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage

The precise control of motor movements is of fundamental importance to all behaviors in the animal kingdom. Efficient motor behavior depends on dedicated neuronal circuits – such as those in the cerebellum – that are controlled by extensive genetic programs. Autosomal recessive cerebellar ataxias (A...

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Autores principales: Eidhof, Ilse, Krebbers, Alina, van de Warrenburg, Bart, Schenck, Annette
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10354283/
https://www.ncbi.nlm.nih.gov/pubmed/37476399
http://dx.doi.org/10.3389/fncir.2023.1148947
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author Eidhof, Ilse
Krebbers, Alina
van de Warrenburg, Bart
Schenck, Annette
author_facet Eidhof, Ilse
Krebbers, Alina
van de Warrenburg, Bart
Schenck, Annette
author_sort Eidhof, Ilse
collection PubMed
description The precise control of motor movements is of fundamental importance to all behaviors in the animal kingdom. Efficient motor behavior depends on dedicated neuronal circuits – such as those in the cerebellum – that are controlled by extensive genetic programs. Autosomal recessive cerebellar ataxias (ARCAs) provide a valuable entry point into how interactions between genetic programs maintain cerebellar motor circuits. We previously identified a striking enrichment of DNA repair genes in ARCAs. How dysfunction of ARCA-associated DNA repair genes leads to preferential cerebellar dysfunction and impaired motor function is however unknown. The expression of ARCA DNA repair genes is not specific to the cerebellum. Only a limited number of animal models for DNA repair ARCAs exist, and, even for these, the interconnection between DNA repair defects, cerebellar circuit dysfunction, and motor behavior is barely established. We used Drosophila melanogaster to characterize the function of ARCA-associated DNA repair genes in the mushroom body (MB), a structure in the Drosophila central brain that shares structural features with the cerebellum. Here, we demonstrate that the MB is required for efficient startle-induced and spontaneous motor behaviors. Inhibition of synaptic transmission and loss-of-function of ARCA-associated DNA repair genes in the MB affected motor behavior in several assays. These motor deficits correlated with increased levels of MB DNA damage, MB Kenyon cell apoptosis and/or alterations in MB morphology. We further show that expression of genes involved in glutamate signaling pathways are highly, specifically, and persistently elevated in the postnatal human cerebellum. Manipulation of glutamate signaling in the MB induced motor defects, Kenyon cell DNA damage and apoptosis. Importantly, pharmacological reduction of glutamate signaling in the ARCA DNA repair models rescued the identified motor deficits, suggesting a role for aberrant glutamate signaling in ARCA-DNA repair disorders. In conclusion, our data highlight the importance of ARCA-associated DNA repair genes and glutamate signaling pathways to the cerebellum, the Drosophila MB and motor behavior. We propose that glutamate signaling may confer preferential cerebellar vulnerability in ARCA-associated DNA repair disorders. Targeting glutamate signaling could provide an exciting therapeutic entry point in this large group of so far untreatable disorders.
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spelling pubmed-103542832023-07-20 Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage Eidhof, Ilse Krebbers, Alina van de Warrenburg, Bart Schenck, Annette Front Neural Circuits Neural Circuits The precise control of motor movements is of fundamental importance to all behaviors in the animal kingdom. Efficient motor behavior depends on dedicated neuronal circuits – such as those in the cerebellum – that are controlled by extensive genetic programs. Autosomal recessive cerebellar ataxias (ARCAs) provide a valuable entry point into how interactions between genetic programs maintain cerebellar motor circuits. We previously identified a striking enrichment of DNA repair genes in ARCAs. How dysfunction of ARCA-associated DNA repair genes leads to preferential cerebellar dysfunction and impaired motor function is however unknown. The expression of ARCA DNA repair genes is not specific to the cerebellum. Only a limited number of animal models for DNA repair ARCAs exist, and, even for these, the interconnection between DNA repair defects, cerebellar circuit dysfunction, and motor behavior is barely established. We used Drosophila melanogaster to characterize the function of ARCA-associated DNA repair genes in the mushroom body (MB), a structure in the Drosophila central brain that shares structural features with the cerebellum. Here, we demonstrate that the MB is required for efficient startle-induced and spontaneous motor behaviors. Inhibition of synaptic transmission and loss-of-function of ARCA-associated DNA repair genes in the MB affected motor behavior in several assays. These motor deficits correlated with increased levels of MB DNA damage, MB Kenyon cell apoptosis and/or alterations in MB morphology. We further show that expression of genes involved in glutamate signaling pathways are highly, specifically, and persistently elevated in the postnatal human cerebellum. Manipulation of glutamate signaling in the MB induced motor defects, Kenyon cell DNA damage and apoptosis. Importantly, pharmacological reduction of glutamate signaling in the ARCA DNA repair models rescued the identified motor deficits, suggesting a role for aberrant glutamate signaling in ARCA-DNA repair disorders. In conclusion, our data highlight the importance of ARCA-associated DNA repair genes and glutamate signaling pathways to the cerebellum, the Drosophila MB and motor behavior. We propose that glutamate signaling may confer preferential cerebellar vulnerability in ARCA-associated DNA repair disorders. Targeting glutamate signaling could provide an exciting therapeutic entry point in this large group of so far untreatable disorders. Frontiers Media S.A. 2023-07-05 /pmc/articles/PMC10354283/ /pubmed/37476399 http://dx.doi.org/10.3389/fncir.2023.1148947 Text en Copyright © 2023 Eidhof, Krebbers, van de Warrenburg and Schenck. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neural Circuits
Eidhof, Ilse
Krebbers, Alina
van de Warrenburg, Bart
Schenck, Annette
Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title_full Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title_fullStr Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title_full_unstemmed Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title_short Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage
title_sort ataxia-associated dna repair genes protect the drosophila mushroom body and locomotor function against glutamate signaling-associated damage
topic Neural Circuits
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10354283/
https://www.ncbi.nlm.nih.gov/pubmed/37476399
http://dx.doi.org/10.3389/fncir.2023.1148947
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