Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1

Abstract

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.

Intranuclear inclusions of polyQ-expanded ATXN1 sequester RNA molecules

“…Indicatively, proteins of cluster 1 were found to participate in ribosome biogenesis while spliceosome, mRNA surveillance and RNA transport were the majorly enriched pathways of cluster 2. Proteins participating in cluster 3 and 4 were highly associated with the ribosome and focal adhesion ( Figure 4A ), in agreement with previous studies reporting perturbation of the protein synthesis machinery and extracellular matrix remodeling in SCA1 ( Lee et al, 2011b ; Vagiona et al, 2020 ).…”

Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

“…Gradual formation of insoluble ATXN1(Q82) protein inclusions in MSCs was accompanied by ROS accumulation and deregulation of pathways involved in oxidative phosphorylation, which is also observed in the cerebellum of SCA1 patients [ 58 ]. More importantly, a proteomics analysis indicated that aggregation of the polyQ-expanded protein was associated with the deregulation of sodium ion transport and the mitochondrial respiratory chain, suggesting a cellular deficiency in ATP synthesis and consequently in energy metabolism [ 59 ].…”

Spinocerebellar Ataxia Type 1 Characteristics in Patient‐Derived Fibroblast and iPSC‐Derived Neuronal Cultures

“…Previously, a computational approach was used to identify dysregulated pathways and genes regulated by CIC, the main driver of pathogenesis in SCA1. The analysis highlighted the important role of MAPK1 and RhoA in an in vitro and in vivo SCA1 protein aggregation model 60 . Remarkably, expression of MAPK1 ( ERK2 ) and RHOA genes was significantly downregulated in SCA1 hiPSC‐derived neurons, whereas their protein products constitute the major components of the disease‐relevant CC1.…”

“…The analysis highlighted the important role of MAPK1 and RhoA in an in vitro and in vivo SCA1 protein aggregation model. 60 Remarkably, expression of MAPK1 (ERK2) and RHOA genes was significantly downregulated in SCA1 hiPSC-derived neurons, whereas their protein products constitute the major components of the disease-relevant CC1. CIC acts as a transcriptional repressor of genes regulated by the MAPK/ERK signaling pathway, 61 whereas phosphorylation and degradation of CIC by MAPK/ERK induces histone acetylation and prolonged translational repression.…”