NURR1 Impairment in Multiple Sclerosis Montarolo, Francesca; Martire, Serena; Perga, Simona ...
International journal of molecular sciences,
09/2019, Letnik:
20, Številka:
19
Journal Article
Recenzirano
Odprti dostop
The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune ...inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson's disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies.
The presence of KIR4.1 antibodies has been proposed to be a characteristic of Multiple Sclerosis (MS). This could have a significant impact on disease management. However, the validation of the ...initial findings has failed till date. Conflicting results have been attributed to difficulties in isolating the lower-glycosylated (LG) KIR4.1 expressed in oligodendrocytes, the putative target antigen of autoantibodies.
The aim of this study is to verify the presence of KIR4.1 antibodies in MS patients, by independently replicating the originally-described procedure.
Assay procedure consisted of KIR4.1 expression in HEK293 cells, 3-step elution to isolate LG-KIR4.1 in elution fraction 3, and ELISA. Sera of 48 MS patients and 46 HCs were studied in 21 working sessions.
In a preliminary analysis, we observed different KIR4.1 antibody levels between MS patients and Healthy Controls (HCs). However, a high variability across working sessions was observed and the sensitivity of the assay was very low. Thus, stringent criteria were established in order to identify working sessions in which the pure LG-KIR4.1 was isolated. As per these criteria, we detected LG-KIR4.1 antibodies in 28% of MS patients and 5% of HCs.
Unlike previous findings, this study is in agreement with the original report. We propose further efforts be made towards the development of a uniform method to establish the detection of KIR4.1 antibodies in MS patients.
•The specificity of KIR4.1 antibodies for MS has been debated in the last few years.•Conflicting data might be due to differences in the assay methodology.•We detected KIR4.1 antibodies in a significant percentage of MS patients, applying rigorous acceptance criteria.•The utilization of the present method hampered in everyday clinical practice due to its complexity.•Further studies are needed to develop an assay that allows easier quantification of KIR4.1 antibodies.
The intracellular-ubiquitin-ending-enzyme tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is a potent inhibitor of the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated ...B cell (NF-kB) pathway. Single nucleotide polymorphisms in TNFAIP3 locus have been associated to autoimmune inflammatory disorders, including Multiple Sclerosis (MS). Previously, we reported a TNFAIP3 down-regulated gene expression level in blood and specifically in monocytes obtained from treatment-naïve MS patients compared to healthy controls (HC). Myeloid cells exert a key role in the pathogenesis of MS. Here we evaluated the effect of specific TNFAIP3 deficiency in myeloid cells including monocytes, monocyte-derived cells (M-MDC) and microglia analyzing lymphoid organs and microglia of mice. TNFAIP3 deletion is induced using conditional knock-out mice for myeloid lineage. Flow-cytometry and histological procedures were applied to assess the immune cell populations of spleen, lymph nodes and bone marrow and microglial cell density in the central nervous system (CNS), respectively. We found that TNFAIP3 deletion in myeloid cells induces a reduction in body weight, a decrease in the number of M-MDC and of common monocyte and granulocyte precursor cells (CMGPs). We also reported that the lack of TNFAIP3 in myeloid cells induces an increase in microglial cell density. The results suggest that TNFAIP3 in myeloid cells critically controls the development of M-MDC in lymphoid organ and of microglia in the CNS.
Abstract We studied the baseline expression level of 25 interferon-regulated genes (MxA, GPR3, IL17RC, ISG15, TRAIL, OASL, IFIT1, IFIT2, RSAD2, OAS3, IFI44L, TRIM22, IL10, CXCL10, STAT1, OAS1, OAS2, ...IFNAR1, IFNAR2, IFNβ, ISG20, IFI6, PKR, IRF7, USP18), recurrently proposed in the literature as predictive biomarkers of interferon-beta treatment response, in whole blood of 10 “responders” and 10 “non-responders” multiple sclerosis relapsing–remitting patients, retrospectively selected on the basis of stringent clinical criteria after a five years follow-up. However, we cannot confirm the predictive value of these candidate biomarkers.
Parkinson’s disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription ...factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer’s disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.
The transcription factor NURR1 regulates the dopamine (DA) signaling pathway and exerts a critical role in the development of midbrain dopaminergic neurons (mDA). NURR1 alterations have been linked ...to DA-associated brain disorders, such as Parkinson's disease and schizophrenia. However, the association between NURR1 defects and the attention-deficit hyperactivity disorder (ADHD), a DA-associated brain disease characterized by hyperactivity, impulsivity and inattention, has never been demonstrated. To date, a comprehensive murine model of ADHD truly reflecting the whole complex human psychiatric disorder still does not exist. NURR1-knockout (NURR1-KO) mice have been reported to exhibit increased spontaneous locomotor activity, but their complete characterization is still lacking. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. As a result, their hyperactive phenotype was confirmed, while their impulsive behavior was reported for the first time. On the other hand, no anxiety and alterations in motor coordination, sociability and memory were observed. Also, the number of mDA expressing tyrosine hydroxylase, a rate-limiting enzyme of catecholamines biosynthesis, and DA level in brain were not impaired in NURR1-KO mice. Finally, hyperactivity has been shown to be recovered by treatment with methylphenidate, the first line psychostimulant drug used for ADHD. Overall, our study suggests that the NURR1 deficient male mouse may be a satisfactory model to study some ADHD behavioral phenotypes and to test the clinical efficacy of potential therapeutic agents.
Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) ...biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Aβ42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Aβ42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.
Multiple sclerosis (MS) is an autoimmune chronic disease of the central nervous system (CNS) characterized by immune-mediated inflammation, demyelination and subsequent axonal damage. Gene expression ...profiling showed that Nurr1, an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells of MS patients. Nurr1 exerts an anti-inflammatory role repressing the activity of the pro-inflammatory transcription factor NF-kB. Here, we report that the preventive treatment with isoxazolo-pyridinone 7e, an activator of Nurr1 signaling pathway, reduces the incidence and the severity of a MS murine model, i.e. experimental autoimmune encephalomyelitis (EAE). The compound is able to attenuate inflammation and neurodegeneration in spinal cords of EAE mice by an NF-kB pathway-dependent process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
