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Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment

Huntington’s disease is a fatal autosomal-dominant neurodegenerative disorder, characterized by neuronal cell dysfunction and loss, primarily in the striatum, cortex and hippocampus, causing motor, cognitive and psychiatric impairments. Unfortunately, no treatments are yet available to modify the pr...

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Autores principales: Mees, Isaline, Li, Shanshan, Tran, Harvey, Ang, Ching-Seng, Williamson, Nicholas A, Hannan, Anthony J, Renoir, Thibault
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9746689/
https://www.ncbi.nlm.nih.gov/pubmed/36523271
http://dx.doi.org/10.1093/braincomms/fcac305
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author Mees, Isaline
Li, Shanshan
Tran, Harvey
Ang, Ching-Seng
Williamson, Nicholas A
Hannan, Anthony J
Renoir, Thibault
author_facet Mees, Isaline
Li, Shanshan
Tran, Harvey
Ang, Ching-Seng
Williamson, Nicholas A
Hannan, Anthony J
Renoir, Thibault
author_sort Mees, Isaline
collection PubMed
description Huntington’s disease is a fatal autosomal-dominant neurodegenerative disorder, characterized by neuronal cell dysfunction and loss, primarily in the striatum, cortex and hippocampus, causing motor, cognitive and psychiatric impairments. Unfortunately, no treatments are yet available to modify the progression of the disease. Recent evidence from Huntington’s disease mouse models suggests that protein phosphorylation (catalysed by kinases and hydrolysed by phosphatases) might be dysregulated, making this major post-translational modification a potential area of interest to find novel therapeutic targets. Furthermore, environmental enrichment, used to model an active lifestyle in preclinical models, has been shown to alleviate Huntington’s disease-related motor and cognitive symptoms. However, the molecular mechanisms leading to these therapeutic effects are still largely unknown. In this study, we applied a phosphoproteomics approach combined with proteomic analyses on brain samples from pre-motor symptomatic R6/1 Huntington’s disease male mice and their wild-type littermates, after being housed either in environmental enrichment conditions, or in standard housing conditions from 4 to 8 weeks of age (n = 6 per group). We hypothesized that protein phosphorylation dysregulations occur prior to motor onset in this mouse model, in two highly affected brain regions, the striatum and hippocampus. Furthermore, we hypothesized that these phosphoproteome alterations are rescued by environmental enrichment. When comparing 8-week-old Huntington’s disease mice and wild-type mice in standard housing conditions, our analysis revealed 229 differentially phosphorylated peptides in the striatum, compared with only 15 differentially phosphorylated peptides in the hippocampus (statistical thresholds fold discovery rate 0.05, fold change 1.5). At the same disease stage, minor differences were found in protein levels, with 24 and 22 proteins dysregulated in the striatum and hippocampus, respectively. Notably, we found no differences in striatal protein phosphorylation and protein expression when comparing Huntington’s disease mice and their wild-type littermates in environmentally enriched conditions. In the hippocampus, only four peptides were differentially phosphorylated between the two genotypes under environmentally enriched conditions, and 22 proteins were differentially expressed. Together, our data indicates that protein phosphorylation dysregulations occur in the striatum of Huntington’s disease mice, prior to motor symptoms, and that the kinases and phosphatases leading to these changes in protein phosphorylation might be viable drug targets to consider for this disorder. Furthermore, we show that an early environmental intervention was able to rescue the changes observed in protein expression and phosphorylation in the striatum of Huntington’s disease mice and might underlie the beneficial effects of environmental enrichment, thus identifying novel therapeutic targets.
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spelling pubmed-97466892022-12-14 Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment Mees, Isaline Li, Shanshan Tran, Harvey Ang, Ching-Seng Williamson, Nicholas A Hannan, Anthony J Renoir, Thibault Brain Commun Original Article Huntington’s disease is a fatal autosomal-dominant neurodegenerative disorder, characterized by neuronal cell dysfunction and loss, primarily in the striatum, cortex and hippocampus, causing motor, cognitive and psychiatric impairments. Unfortunately, no treatments are yet available to modify the progression of the disease. Recent evidence from Huntington’s disease mouse models suggests that protein phosphorylation (catalysed by kinases and hydrolysed by phosphatases) might be dysregulated, making this major post-translational modification a potential area of interest to find novel therapeutic targets. Furthermore, environmental enrichment, used to model an active lifestyle in preclinical models, has been shown to alleviate Huntington’s disease-related motor and cognitive symptoms. However, the molecular mechanisms leading to these therapeutic effects are still largely unknown. In this study, we applied a phosphoproteomics approach combined with proteomic analyses on brain samples from pre-motor symptomatic R6/1 Huntington’s disease male mice and their wild-type littermates, after being housed either in environmental enrichment conditions, or in standard housing conditions from 4 to 8 weeks of age (n = 6 per group). We hypothesized that protein phosphorylation dysregulations occur prior to motor onset in this mouse model, in two highly affected brain regions, the striatum and hippocampus. Furthermore, we hypothesized that these phosphoproteome alterations are rescued by environmental enrichment. When comparing 8-week-old Huntington’s disease mice and wild-type mice in standard housing conditions, our analysis revealed 229 differentially phosphorylated peptides in the striatum, compared with only 15 differentially phosphorylated peptides in the hippocampus (statistical thresholds fold discovery rate 0.05, fold change 1.5). At the same disease stage, minor differences were found in protein levels, with 24 and 22 proteins dysregulated in the striatum and hippocampus, respectively. Notably, we found no differences in striatal protein phosphorylation and protein expression when comparing Huntington’s disease mice and their wild-type littermates in environmentally enriched conditions. In the hippocampus, only four peptides were differentially phosphorylated between the two genotypes under environmentally enriched conditions, and 22 proteins were differentially expressed. Together, our data indicates that protein phosphorylation dysregulations occur in the striatum of Huntington’s disease mice, prior to motor symptoms, and that the kinases and phosphatases leading to these changes in protein phosphorylation might be viable drug targets to consider for this disorder. Furthermore, we show that an early environmental intervention was able to rescue the changes observed in protein expression and phosphorylation in the striatum of Huntington’s disease mice and might underlie the beneficial effects of environmental enrichment, thus identifying novel therapeutic targets. Oxford University Press 2022-11-21 /pmc/articles/PMC9746689/ /pubmed/36523271 http://dx.doi.org/10.1093/braincomms/fcac305 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Mees, Isaline
Li, Shanshan
Tran, Harvey
Ang, Ching-Seng
Williamson, Nicholas A
Hannan, Anthony J
Renoir, Thibault
Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title_full Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title_fullStr Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title_full_unstemmed Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title_short Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment
title_sort phosphoproteomic dysregulation in huntington’s disease mice is rescued by environmental enrichment
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9746689/
https://www.ncbi.nlm.nih.gov/pubmed/36523271
http://dx.doi.org/10.1093/braincomms/fcac305
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