Genetic analysis of the LAMP-2 gene promoter in patients with sporadic Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease in the people of over 65. Majority of PD is sporadic, which is caused by interaction of genetic and environmental factors. To date, genetic causes and underlying molecular mechanisms for sporadic PD remain largely unknown. Autophagy is a conserved cellular degradative process, consisting of macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy (hereafter referred to as autophagy) and CMA are involved in the degradation of alpha-synuclein, a critical protein in the PD pathogenesis. Previous studies with brain tissues and leukocytes have shown that the expression levels of lysosome-associated membrane-2 (LAMP-2) gene are significantly decreased in PD patients. In this study, we genetically and functionally analyze the promoter region of LAMP-2 gene in sporadic PD patients. Two novel sequence variants and two single nucleotide polymorphisms (SNPs) were identified. The heterozygous variant, g.4127A>C, which was only found in one female PD patient, significantly reduced the transcriptional activities of LAMP-2 gene promoter. The hemizygous variant, g.5038G>A, which was only found in one male control, enhanced the transcriptional activities of LAMP-2 gene promoter. No significant difference in frequencies of the SNPs, rs42900 (g.4569A>C) and rs28603270 (g.4760T>G), was observed between PD patients and controls. Collectively, the sequence variants within the LAMP-2 gene promoter may be linked to the PD onset by changing LAMP-2 protein levels and impairing autophagy and CMA activities.