Abstract
In Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson’s disease.Graphical abstract
Highlights
Midbrain dopaminergic (DAergic) neurons are the main source of dopamine (DA) in the mammalian central nervous system
Results α‐SYN Aggregates Reduce the DAergic Phenotype of SH‐SY5Y Cells In order to identify the mechanism involved in the dysregulation of the DAergic phenotype, we incubated the DAergic cell line SH-SY5Y with preformed fibrils (PFFs) of human recombinant α-SYN (1 μg/ml, 10 days)
The effect was most evident in the GSK-3β knocked-down cells, indicating a preponderant role for this isoform. These results show for the first time that glycogen synthase kinase-3 (GSK-3) is required for the downregulation of nuclear receptor‐related factor 1 (NURR1) induced by α-SYN and are in line with observations based on GSK-3 inhibitors in the Parkinsonian MPTP and M PP+ [53, 54], or 6-OHDA [55,56,57] models
Summary
Midbrain dopaminergic (DAergic) neurons are the main source of dopamine (DA) in the mammalian central nervous system. Molecular Neurobiology functionality during adulthood [2,3,4]. It regulates the expression of several genes involved in DA metabolism, including tyrosine hydroxylase (TH) [5,6,7], dopamine transporter (DAT) [8], amino acid decarboxylase (AADC) [9], vesicular monoamine transporter-2 (VMAT2) [9], as well as other nonDAergic genes such as NRP1 [10] and RET (GDNF receptor) [11]. Ablation of NURR1 in adult rodents results in reduced expression of its target genes and loss of functional DAergic midbrain neurons [12,13,14]. Mutations in the human NURR1 gene have been identified in association with Parkinson’s disease (PD), where neurodegeneration of the DAergic neurons of the SN occurs [15, 16]
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