Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1.
ataxin-1
blood-brain-barrier
drugs
network
pathway
polyQ
Journal
Genes
ISSN: 2073-4425
Titre abrégé: Genes (Basel)
Pays: Switzerland
ID NLM: 101551097
Informations de publication
Date de publication:
25 09 2020
25 09 2020
Historique:
received:
20
08
2020
revised:
14
09
2020
accepted:
23
09
2020
entrez:
30
9
2020
pubmed:
1
10
2020
medline:
16
7
2021
Statut:
epublish
Résumé
Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo. Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1). A set of common dysregulated pathways were identified, which were utilized to construct cerebellum-specific protein-protein interaction (PPI) networks at various time-points of protein aggregation. Analysis of a SCA1 network indicated important nodes which regulate its function and might represent potential pharmacological targets. Furthermore, a set of drugs interacting with these nodes and predicted to enter the blood-brain barrier (BBB) was identified. Our study points to molecular mechanisms of SCA1 linked from both cellular and animal models and suggests drugs that could be tested to determine whether they affect the aggregation of pathogenic ATXN1 and SCA1 disease progression.
Sections du résumé
BACKGROUND
Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo.
METHODS
Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1).
RESULTS
A set of common dysregulated pathways were identified, which were utilized to construct cerebellum-specific protein-protein interaction (PPI) networks at various time-points of protein aggregation. Analysis of a SCA1 network indicated important nodes which regulate its function and might represent potential pharmacological targets. Furthermore, a set of drugs interacting with these nodes and predicted to enter the blood-brain barrier (BBB) was identified.
CONCLUSIONS
Our study points to molecular mechanisms of SCA1 linked from both cellular and animal models and suggests drugs that could be tested to determine whether they affect the aggregation of pathogenic ATXN1 and SCA1 disease progression.
Identifiants
pubmed: 32992839
pii: genes11101129
doi: 10.3390/genes11101129
pmc: PMC7600199
pii:
doi:
Substances chimiques
Ataxin-1
0
Atxn1 protein, mouse
0
Nerve Tissue Proteins
0
Peptides
0
polyglutamine
26700-71-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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