Novel and functional ABCB1 gene variant in sporadic Parkinson鈥檚 disease

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• 作者：Yuequn Li^a ; ¹ ; Yonghua Li^b ; ¹ ; Shuchao Pang^c ; ¹ ; Wenhui Huang^c ; Aimei Zhang^d ; Robert G. Hawley^e ; ^f ; ^{rghawley@gwu.edu" class="auth_mail} ; Bo Yan^c ; ^e ; ^f ; ^{yanbo@mail.jnmc.edu.cn" class="auth_mail} ; ^{yanbo@gwu.edu" class="auth_mail} ; ^{yanbmd@gmail.com" class="auth_mail}
• 关键词：ABCB1 ; ATP-binding cassette sub-family B member 1 ; ATP13A2 ; Lysosomal P-type transmembrane cation-transporting ATPase ; PARK9 ; BBB ; Blood&ndash ; brain barrier ; DJ-1 ; PARK7 gene ; DSVs ; DNA sequence variants ; FOXO1 ; Forkhead box factor O1 ; FOXO3a ; Forkhead box factor O3a ; GBA ; Lysosomal 尾-glucocerebrosidase ; LRRK1 ; Leucine-rich repeat kinase 1 ; PD ; Parkinson&rsquo ; s disease ; PINK1 ; PTEN-induced kinase 1 ; SNCA ; Alpha-synuclein gene ; SNPs ; Single-nucleic acid polymorphisms ; SP1 ; Specificity protein 1
• 刊名：Neuroscience Letters
• 出版年：30 April, 2014
• 年：2014
• 卷：566
• 期：Complete
• 页码：61-66
• 全文大小：1514 K

文摘

Parkinson鈥檚 disease (PD) is a common progressive neurodegenerative disease. Most cases of PD are sporadic, which is caused by interaction of genetic and environmental factors. To date, genetic causes for sporadic PD remain largely unknown. ATP-binding cassette sub-family B member 1 (ABCB1) is a membrane-associated protein that acts as an efflux transporter for many substrates, including chemotherapeutic agents, anti-epilepsy medicine, antibiotics and drugs for PD. ABCB1 gene is widely expressed in human tissues, including endothelial cells of capillary blood vessels at blood-brain barrier sites. In PD patients, decreased ABCB1 levels have been reported. We speculated that misregulation of ABCB1 gene expression, caused by DNA sequence variants (DSVs) within its regulatory regions, may be involved in PD development. In this study, we genetically and functionally analyzed the proximal promoter of the human ABCB1 gene, which is required for constitutive expression, in sporadic PD patients and healthy controls. The results showed that a novel and heterozygous DSV g.117077G>A was identified in one PD patient, but in none of the controls. This DSV significantly altered the transcriptional activity of the ABCB1 gene promoter in transiently transfected HEK-293 cells. A heterozygous DSV g.116347T>C was only found in one control. Four single-nucleotide polymorphisms, g.116154T>C (rs28746504), g.117130A>G (rs2188524), g.117356C>G (rs34976462) and g.117372T>C (rs3213619), and one heterozygous deletion DSV g.116039del were found in PD patients and controls with similar frequencies. Therefore, our findings suggest that ABCB1 gene promoter DSVs may contribute to PD development as a rare risk factor.