Nurr1 repression mediates cardinal features of Parkinson’s disease in α-synuclein transgenic mice

Abstract

Duplication/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson’s disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)/Nurr1+/− (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. Aging ‘2-hit’ mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. Pathological abnormalities of phenotypic mice included SN neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. Mice with two wt Nurr1 alleles [ASYN(d)/Nurr1+/+] or with reduced ASYN load [ASYN(s)/Nurr1+/−] did not develop the phenotype or pathology. Critically, we found that aging ASYN(d), in contrast to ASYN(s), mice suppress Nurr1-protein levels in a brain region–specific manner, which in addition to Nurr1 hemizygosity is necessary to instigate PD pathogenesis. Our experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation.

Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology

“…García-Yagüe et al (2021) showed that activation of GSK-3β by toxic α-SYN leads to phosphorylation and subsequent UPS degradation of NURR1, leading to loss of DAergic markers [16]. The relationship between α-SYN and NURR1 was previously described in Yuan et al (2008), who reported that overexpression of the toxic form α-SYN regulates the expression levels of NF-κB and increases the activity of glycogen synthase kinase 3β (GSK-3β) in DAergic neurons, which would have adverse effects on the NURR1 levels [16,100,101]. Mechanistically, this group identified the putative "MAP-Kinase's motif" between (124-PSSPPTPSTP-133) amino acids, harbouring proline-directed serine residues, as the main target of this kinase.…”

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson’s Disease-Associated Neurodegeneration

“…Recent research has demonstrated the importance of the Lmx1a-miR-204/211-Nurr1 axis in the differentiation of mDA neurons [58]. Additionally, mice that are overexpressed with mutant alpha-synuclein and simultaneously lacking one Nurr1 allele showed the enhanced age-dependent reduction of Nurr1 protein levels, a decreased number of mDA neurons, as well as increased neuroinflammation and alpha-synuclein aggregation [59]. The possible mechanism underlying these pathological phenotypes is that alpha-synuclein promoted the GSK3B-mediated phosphorylation (a component of the Wnt1/β-catenin pathway) and the subsequent proteasomal degradation of Nurr1 [60], suggesting the presence of a Wnt1/β-catenin-lmx1a-Nurr1 pathway in the differentiation of mDA neurons.…”

The role of NURR1 in metabolic abnormalities of Parkinson’s disease

“…A decrease in SNpc NURR1 expression was also observed in some progressive supranuclear palsy and Alzheimer’s disease patients [ 42 ], indicating that reducing NURR1 in DAergic neurons is linked to intracellular pathology in synucleinopathies and tauopathies. NURR1 expression in the SNpc of α-synuclein homozygous mice significantly decreased with age [ 80 ]. Similar findings were achieved when the α-synuclein preformed fibril was injected into the putamen of non-human primates [ 81 ].…”