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Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we use...

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Autores principales: Roth, Jonathan R., de Moraes, Ruan Carlos Macedo, Xu, Brittney P., Crawley, Savannah R., Khan, Malghalara A., Melkani, Girish C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562706/
https://www.ncbi.nlm.nih.gov/pubmed/37823007
http://dx.doi.org/10.3389/fnagi.2023.1223911
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author Roth, Jonathan R.
de Moraes, Ruan Carlos Macedo
Xu, Brittney P.
Crawley, Savannah R.
Khan, Malghalara A.
Melkani, Girish C.
author_facet Roth, Jonathan R.
de Moraes, Ruan Carlos Macedo
Xu, Brittney P.
Crawley, Savannah R.
Khan, Malghalara A.
Melkani, Girish C.
author_sort Roth, Jonathan R.
collection PubMed
description Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.
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spelling pubmed-105627062023-10-11 Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila Roth, Jonathan R. de Moraes, Ruan Carlos Macedo Xu, Brittney P. Crawley, Savannah R. Khan, Malghalara A. Melkani, Girish C. Front Aging Neurosci Aging Neuroscience Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain. Frontiers Media S.A. 2023-09-26 /pmc/articles/PMC10562706/ /pubmed/37823007 http://dx.doi.org/10.3389/fnagi.2023.1223911 Text en Copyright © 2023 Roth, Moraes, Xu, Crawley, Khan and Melkani. 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 Aging Neuroscience
Roth, Jonathan R.
de Moraes, Ruan Carlos Macedo
Xu, Brittney P.
Crawley, Savannah R.
Khan, Malghalara A.
Melkani, Girish C.
Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title_full Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title_fullStr Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title_full_unstemmed Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title_short Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
title_sort rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in drosophila
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562706/
https://www.ncbi.nlm.nih.gov/pubmed/37823007
http://dx.doi.org/10.3389/fnagi.2023.1223911
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