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Abstract: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1α can be stimulated via oxygen (O2)-independent mechanisms; whereas, the degradation of HIF-1α is regulated via Fe2+ and/or O2-dependent enzyme prolyl hydroxylase (PHD). Aberrant iron accumulation, mitochondrial dysfunction and impairment of protein degradation system, such as autophagy, have been implicated in the pathogenesis of Parkinson''s disease, among which, iron and mitochondrial dysfunction may enhance the enzyme activity of prolyl hydroxylase and cause the decrease of HIF-1α. Recent reports have indicated that HIF-1α may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1α under the pathogenesis of Parkinson''s disease, we speculated that compounds that might stabilize HIF-1α could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1α due to the decreased degradation of HIF-1αvia inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1α was decreased in rotenone or MPP+-treated SH-SY5Y cell models of Parkinson''s disease. We demonstrated that deferoxamine caused accumulation of HIF-1α accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1α gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1α. Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1α or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1α was decreased under the situation when mitochondrial complex I was inhibited, and the neuroprotective role of deferoxamine in rotenone-induced apoptosis could be partially explained by its effects on the accumulation of HIF-1α and HIF-1α-mediated induction of autophagy. [Copyright &y& Elsevier]

Abstract: The nuclear receptor related 1 (Nurr1) transcription factor contributes to the development and maintenance of dopamine (DA) neurons in the brain. We found that heterozygous Nurr1 knockout (Nurr1 +/−) influenced the age-dependent decline in the number of DA neurons and influenced DA signaling. We examined the DA marker, tyrosine hydroxylase, using immunohistochemistry, and we measured DA signaling using fast-scan cyclic voltammetry in 3 age groups of wild-type (Nurr1 +/+) and mutant (Nurr1 +/−) mice: 3–6, 9–12, and 15–23 mo old. Prior to significant loss of DA neurons and to the onset of parkinsonian symptoms, young Nurr1 +/− mice (3–6 mo) exhibited a decrease in peak evoked DA release that was partially countered by a decrease in the rate of DA reuptake. As peak evoked DA release declined with age for both the wild-type and Nurr1 +/− mice, both genotypes manifested decreased DA reuptake. As the DA release fell further with age, decreased DA reuptake eventually could not adequately compensate the Nurr1 +/− mice. The results indicated that Nurr1 deficiency led to impaired DA release even before significant DA neuron loss. [Copyright &y& Elsevier]

Abstract: PITX3 is a transcription factor important for the differentiation and survival of midbrain dopaminergic neurons during the development. Recent reports suggest that single nucleotide polymorphisms (SNP) in the gene may be associated with Parkinson''s disease (PD). To verify their findings and to determine the nature of the association in a subset of our PD patients we have analyzed two PITX3 SNPs (rs2281983 and rs4919621) in 265 PD patients and compared them with 210 age-matched healthy controls. Our data show that the substitutions of C/T in SNP1 and A/T in SNP2 are significantly higher in PD, and this finding is even more robust in young onset and familial PD as compared with age-matched healthy controls. Our findings indicate that PITX3 may play a role in the pathogenesis of PD. [Copyright &y& Elsevier]

Abstract: NURR1 is a transcription factor essential for the development, survival, and functional maintenance of midbrain dopaminergic (DAergic) neurons and NURR1 is a potential susceptibility gene for Parkinson''s disease (PD). To determine whether NURR1 gene expression is altered in patients with PD, we measured its expression in human peripheral blood lymphocytes (PBL) in 278 patients with PD, 166 healthy controls (HC), and 256 neurological disease controls (NDC) by quantitative real-time PCR. NURR1 gene expression was significantly decreased in patients with PD (particularly those with family history of PD) as compared with HC (p <0.01) and also as compared with NDC (p <0.05). There was no significant difference in NURR1 gene expression among PD patients with or without anti-PD medications. When adjusted for gender, age, and ethnicity, lower levels of NURR1 gene expression were associated with significantly increased risk for PD in women, in patients 60 years old or older, and in patients of Caucasian origin. The observed reduction in PBL NURR1 gene expression indicates possible systemic involvement in PD, and the finding may help identify individuals with PD and other disorders associated with impaired central DAergic system. [Copyright &y& Elsevier]

Abstract: The proneural protein Neurogenin 2 (NEUROG2) is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons. To determine whether genetic variation in the coding region of the NEUROG2 gene plays a role in the etiology of Parkinson''s disease (PD), we screened DNA samples from 202 PD patients and 201 normal controls. No mutation in the NEUROG2 gene was identified in our PD cohort, except that novel compound heterozygous variants (Gly56Arg and Asp206Glu) were found in a 91-year normal male, suggesting that mutations in the coding region of the NEUROG2 gene play little or no role in the development of PD. [Copyright &y& Elsevier]