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Widespread alterations in microRNA biogenesis in human Huntington’s disease putamen

Petry, Serena ; Keraudren, Rémi ; Nateghi, Behnaz ; Loiselle, Andréanne ; Pircs, Karolina LU orcid ; Jakobsson, Johan LU orcid ; Sephton, Chantelle ; Langlois, Mélanie ; St-Amour, Isabelle and Hébert, Sébastien S. (2022) In Acta Neuropathologica Communications 10.
Abstract

Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the... (More)

Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at the early stages of the disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in the HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ago2, Autophagy, Biogenesis, Dicer, Huntington’s disease, microRNA, RNAi
in
Acta Neuropathologica Communications
volume
10
article number
106
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85134563706
  • pmid:35869509
ISSN
2051-5960
DOI
10.1186/s40478-022-01407-7
language
English
LU publication?
yes
id
2c525e07-1ce8-4d2f-8cf3-f755bf3ecd3f
date added to LUP
2022-09-23 15:15:46
date last changed
2024-06-25 02:54:02
@article{2c525e07-1ce8-4d2f-8cf3-f755bf3ecd3f,
  abstract     = {{<p>Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at the early stages of the disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in the HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.</p>}},
  author       = {{Petry, Serena and Keraudren, Rémi and Nateghi, Behnaz and Loiselle, Andréanne and Pircs, Karolina and Jakobsson, Johan and Sephton, Chantelle and Langlois, Mélanie and St-Amour, Isabelle and Hébert, Sébastien S.}},
  issn         = {{2051-5960}},
  keywords     = {{Ago2; Autophagy; Biogenesis; Dicer; Huntington’s disease; microRNA; RNAi}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Acta Neuropathologica Communications}},
  title        = {{Widespread alterations in microRNA biogenesis in human Huntington’s disease putamen}},
  url          = {{http://dx.doi.org/10.1186/s40478-022-01407-7}},
  doi          = {{10.1186/s40478-022-01407-7}},
  volume       = {{10}},
  year         = {{2022}},
}