<scp>NURR1</scp>‐deficient mice have age‐ and sex‐specific behavioral phenotypes

Montarolo, Francesca; Martire, Serena; Chiara, Francesco Di; Allegra, Sarah; Francia, Silvia De; Hoxha, Eriola; Tempia, Filippo; Capobianco, Marco; Bertolotto, Antonio

doi:10.1002/jnr.25067

Cited by 8 publications

(5 citation statements)

References 49 publications

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“…However, changes in the challenging beam in pesticide exposed PFF-PD model have been seen only in males, and this was not related to bigger nigral TH loss or α-syn pathology, but to dopamine turnover and inflammatory changes 72 . A predominant affection in males has been also seen in other PD relevant studies in mice 73,74 , and male MPTP-intoxicated monkeys showed higher inflammation markers than females 75 . Such observation suggests that the immune response significantly influences the motor phenotype particularly in males.…”

Section: Discussionsupporting

confidence: 72%

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Ferreira

Li²,

Klæstrup

et al. 2022

Preprint

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The aggregation of alpha-synuclein (a-syn) and immune activation are both pathological events related to the neurodegenerative process in Parkinson's disease (PD). The PD-associated immune response involves both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. CD163 is a scavenger receptor specifically expressed in the monocytic lineage, but normally not in microglia. Therefore, the presence of CD163 positive cells into the brain in PD rodent models and in PD patients suggest a monocytic infiltration or otherwise ectopic CD163 expression. In addition, changes in CD163 expression profiles observed in PD patients might indicate a role for CD163-expressing cells in the disease. To elucidate the relevance of the CD163 receptor in the a-syn-induced immune events in PD and associated degeneration we injected murine a-syn pre-formed fibrils (PFF), or monomeric a-syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of a-syn PFF in CD163KO females led to impaired early immune responses as revealed by the lack of ability to upregulate MHCII, CD68, GFAP, and promote CD4 and CD8 T cell infiltration after a-syn PFF injection. An early and long-lasting sensorimotor impairment was observed in a-syn PFF CD163KO males but not in the females. Transcriptomic analysis revealed that CD163 deletion induced phenotypic changes of macrophages and microglia in the brain that potentially impact the motor behavior and neuronal health induced by a-syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and a-syn pathology associated with autophagic defects, which ultimately led to increased dopaminergic neurodegeneration. Overall, our results support a novel sex-dimorphic neuroprotective role for CD163 in the a-syn-induced neuropathology and immune response.

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Section: Discussionsupporting

confidence: 72%

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Ferreira

Li²,

Klæstrup

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…However, changes in the challenging beam in pesticide exposed PFF-PD model have been seen only in males, which was not related to bigger nigral TH loss or α-syn pathology, but to dopamine turnover and inflammatory changes 69 . A male-predominant affection has also been seen in other PD-relevant studies in mice 70 , 71 , and male MPTP-intoxicated monkeys showed higher inflammation markers than females 72 . This suggests that the immune environment significantly influences the motor phenotype, particularly in males, potentially mediated by soluble cytokines 73 , 74 or peripheral cell infiltration, impacting microglia and neuronal function/firing 75 .…”

Section: Discussionsupporting

confidence: 69%

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Ferreira,

Li,

Klæstrup

et al. 2023

npj Parkinsons Dis.

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Alpha-synuclein (α-syn) aggregation and immune activation represent hallmark pathological events in Parkinson’s disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such a response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine α-syn pre-formed fibrils in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to α-syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a sex-dimorphic neuroprotective role for CD163 during α-syn-induced neurodegeneration.

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“…The expression of Nurr1 in midbrain DAergic neurons decreases with age, which coincides with the increased incidence of PD [17]. Montarolo et al found that Nurr1 deficiency triggered alterations in DA levels [60]. In recent years, many compounds have been shown neuroprotective effects by activating Nurr1.…”

Section: Discussionmentioning

confidence: 98%

L-Ergothioneine ameliorates MPTP-induced Parkinson's disease in C57BL/6J mice by activating DJ-1

Meng,

Hou

et al. 2024

Food Science and Human Wellness

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Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The loss of dopaminergic (DAergic) neurons in the substantia nigra and the decrease of dopamine (DA) levels accelerate the process of PD. L-Ergothioneine (EGT) is a natural antioxidant derived from microorganisms, especially in edible mushrooms. EGT can penetrate blood-brain barrier and its levels are significantly decreased in the plasma of PD patients. Therefore, we speculated that EGT could ameliorate PD, and determined its effect on PD development by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models and neurotoxin 1-methyl-4-phenylpyridinium (MPP + )-induced cell models. Our results show that EGT alleviated MPTP-induced behavioral dysfunction in mice. Mechanistically, we innovatively revealed that EGT is a key regulator of DJ-1. EGT restored DA levels by activating the DJ-1-Nuclear receptor-related factor 1(Nurr1) axis. Furthermore, it reduced reactive oxygen species (ROS) levels by regulating the DJ-1-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which inhibited oxidative stress-induced DAergic neuronal apoptosis. Combined treatment with DJ-1-siRNA transfection revealed that blocking DJ-1 reversed EGT upregulated Nurr1 and Nrf2 expression in the nucleus, which significantly decreased the benefits of EGT. Taken together, our study suggests that EGT can ameliorate PD and be considered as a strategy for PD treatment.

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NURR1‐deficient mice have age‐ and sex‐specific behavioral phenotypes

Cited by 8 publications

References 49 publications

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

L-Ergothioneine ameliorates MPTP-induced Parkinson's disease in C57BL/6J mice by activating DJ-1

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