Genetic analysis of lysosomal alpha-galactosidase A gene in sporadic Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease. Majority of PD cases are sporadic, resulting from interaction of genetic and environmental factors. Accumulating evidence indicates that autophagy, which delivers alpha-synuclein to lysosomes for degradation, is involved in the PD pathogenesis. Some lysosomal hydrolases, such as glucocerebrosidase gene and ATP13A2, a lysosomal ATPase gene, have been implicated in PD. We have previously screened the activities of a group of lysosomal hydrolases in sporadic PD patients and found that alpha-galactosidase A (GLA) activities are significantly decreased. In this study, we analyzed GLA gene in sporadic PD patients by sequencing its promoter and exon regions. One single-nucleotide polymorphism (SNP) in the promoter region, rs3027580 (NG_007119.1:g.4292G>C), and two SNPs in the GLA 5′-untranslated region, rs2071225 (NM_000169.2:c.−10C>T) and rs3027585 (NM_000169.2:c.−12G>A), were identified with similar frequencies in sporadic PD patients and healthy controls. A novel variant (NG_007119.1:g.4488C>G) within the promoter region, at the −573 site upstream of the translation start codon (ATG), was found in one male PD patient, but not in female PD patients or healthy controls. Our data suggest that the sequence variant may affect GLA gene expression by altering transcription factor binding sites, contributing to the pathogenesis of sporadic PD.

► GLA gene was bi-directionally sequenced in sporadic PD patients and controls.
► Three SNPs were found in PD patients and controls with similar frequencies.
► A novel variant of GLA gene promoter region was identified in sporadic PD patient.
► Mutations in the GLA coding region were not found.
► Our data suggest that GLA promoter variants may be linked to sporadic PD.