The effect of a promoter polymorphism on the transcription of nitric oxide synthase 1 and its relevance to Parkinson's disease

Abstract

Transcriptional changes of the enzyme nitric oxide synthase I (NOS1) are believed to play a role in the development of many diseases. The gene for NOS1 has 12 alternative first exons (1A-1L). The 1F exon is one of the most highly utilized first exons in the brain and has a polymorphism ((TG)(m)TA(TG)(n)) located in its promoter region. The polymorphism's length has been suggested to affect NOS1 transcription and play a role in Parkinson's disease (PD); however, the actual influence of the polymorphism on NOS1 transcription has not been studied. To better characterize the links of the polymorphism with PD, a genotyping study was done comparing polymorphism length among 170 PD patients and 150 age-matched controls. The pattern of changes between the two group's allele frequencies shows statistical significance (P = 0.0359). The smallest polymorphism sizes are more predominant among PD patients than controls. To study the effects of this polymorphism on NOS1 gene transcription, reporter gene constructs were made by cloning the NOS1 1F promoter with polymorphism lengths of either 42, 54, or 62 bp in front of the luciferase gene and transfecting them into HeLa or Sk-N-MC cells. NOS1-directed reporter gene constructs with the 62-bp polymorphism increased transcription of luciferase 2.2-fold in HeLa and 1.8-fold in Sk-N-MC cells compared with reporter gene constructs with the 42-bp polymorphism. These data suggest that if smaller polymorphism size contributes to the higher NOS1 levels in PD patients, an as yet unknown transcriptional mechanism is required.

The effect of a functional NOS1 promoter polymorphism on impulsivity is moderated by platelet MAO activity

“…The expression of NOS1 in different tissues seems to be mediated by the untranslated leader exon; exons 1c and 1f are the predominant first exons expressed in the human brain (Bros et al 2006;Reif et al 2006). A repeat polymorphism in the promoter region of NOS1 exon 1f (Ex1f-VNTR) which affects gene expression and neuronal transcriptome (Reif et al 2009;Rife et al 2009) is linked to severity of schizophrenia (Reif et al 2006) and Alzheimer's disease (Galimberti et al 2007). Recently, it was found that NOS1 Ex1f-VNTR as well influences aggression, hyperactivity, cluster B personality disorders and impulsivityrelated personality phenotypes in humans (Reif et al 2009).…”

Association of Polymorphism of Neuronal Nitric Oxide Synthase Gene with Risk to Parkinson’s Disease

“…Although nNOS interacts with environmental risk factors associated with PD [10,11], conflicting results deny this notion. A few SNPs in nNOS are found to be associated with PD risk in a population while the same SNPs are not found to be associated in other population [10,[12][13][14][15]. Although lack of association in a few studies [13,16] is reported, it is widely accepted that nNOS polymorphism acts as modifiable factor of PD risk.…”

“…Owing to variation in environment and lifestyle factors as well as ethnicity of north Indians as compared with the rest of the world, it was worthwhile to investigate the association of NOS1 SNPs with PD risk. Since two SNPs located in exon 18 and exon 29 of nNOS gene exhibit variable association with PD risk in different populations [10,[12][13][14][15][16][17], the current study aimed to investigate their association with PD risk and also with nitrosative and oxidative stress indicators.…”

Treatment strategies for Parkinson’s disease

“…Changes in the transcription level of NOS1 are believed to play a role in the development of many diseases [52] . NOS inhibitors may be useful to treat L-Dopa-induced dyskinesia [53] .…”