In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organisms' lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson's disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared to patients with diagnoses of Progressive Supranuclear Palsy (PSP), Alzheimer's disease (AD), or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing α-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and optical density (OD) was observed within substantia nigra (SN) neurons in PD, but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of TH immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.Keywords transcription factor; dopaminergic neuron; α-synuclein; neurofilament; substantia nigra Nurr1, an orphan member of the nuclear receptor superfamily, is highly expressed in the developing and adult ventral midbrain and is required for the acquisition and maintenance of the dopaminergic phenotype in nigrostriatal neurons (Zetterstrom et al., 1997; SaucedoCardenas et al., 1998;Sacchetti et al., 2001;Hermanson et al., 2003;Chu et al., 2002). In the absence of Nurr1, developing ventral midbrain neurons fail to express the dopaminergic (DA) neuronal markers, tyrosine hydroxylase (TH) and dopamine transporter (DAT), as well as the receptor tyrosine kinase signaling subunit Ret (Zetterstrom et al., 1997; SaucedoCardenas et al., 1998;Wallen et al., 2001;Sacchetti et al., 2001;Kim et al., 2003;Kim et al., 2002). Moreover, Nurr1 deficient embryonic ventral midbrain neurons are unable to innervate their striatal target area (Saucedo-Cardenas et al., 1998;Zetterstrom et al., 1997). Newborn heterozygous (Nurr1 -/+ ) mice show significantly reduced levels of Nurr1 and (Eells et al., 2002). Adult heterozygous mice (Nurr1 -/+ ), while otherwise apparently normal, are significantly more sensitive to the toxic effects of 1-methyl-4 phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP) than their wild-type littermates (Le et al., 1999), indicating that Nurr1 influences the ability of DA neur...
Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.
Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.
Nuclear receptor-related factor 1 (Nurr1), a member of the nuclear receptor superfamily, is associated with the induction of dopaminergic (DA) phenotypes in developing and mature midbrain neurons. It is well established that dopaminergic nigrostriatal function decreases with age. Whether age-related deficits in DA phenotypic markers are associated with alterations in Nurr1 expression is unknown. The present study found that virtually all of tyrosine hydroxylase-immunoreactive (TH-ir) neurons within the young adult human substantia nigra were Nurr1-immunoreactive (Nurr1-ir) positive. Stereologic counts revealed a significant reduction in the number of Nurr1-ir nigral neurons in middle-aged (23.13%) and aged (46.33%) individuals relative to young subjects. The loss of Nurr1-ir neurons was associated with a similar decline in TH-ir neuron number. In this regard, TH-ir neuronal number was decreased in middle-aged (11.10%) and in aged (45.97%) subjects, and this loss of TH-ir neurons was highly correlated (r = 0.92) with the loss of Nurr1-ir neurons. In contrast, the number of melanin-containing nigral neuron number was generally stable across age groups, indicating that changes in Nurr1 and TH reflect phenotypic age-related changes and not frank neuronal degeneration. In support of this concept, confocal microscopic analyses of Nurr1-ir and TH-ir fluorescence intensity revealed parallel decreases in Nurr1- and TH-immunofluorescence as a function of age. These data demonstrate that age-related decline of DA phenotypic markers is associated with down-regulation of Nurr1 expression in the SN.
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