An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson’s disease

Abstract

Background Aldehyde dehydrogenase 1 (encoded by ALDH1A1) has been shown to protect against Parkinson’s disease (PD) by reducing toxic metabolites of dopamine. We herein revealed an antisense Alu element insertion/deletion polymorphism in intron 4 of ALDH1A1, and hypothesized that it might play a role in PD. Methods A Han Chinese cohort comprising 488 PD patients and 515 controls was recruited to validate the Alu insertion/deletion polymorphism following a previous study of tag-single nucleotide polymorphisms, where rs7043217 was shown to be significantly associated with PD. Functional analyses of the Alu element insertion were performed. Results The Alu element of ALDH1A1 was identified to be a variant of Yb8 subfamily and termed as Yb8c4. The antisense Yb8c4 insertion/deletion polymorphism (named asYb8c4ins and asYb8c4del, respectively) appeared to be in a complete linkage disequilibrium with rs7043217 and was validated to be significantly associated with PD susceptibility with asYb8c4ins serving as a risk allele (P = 0.030, OR = 1.224, 95% CI = 1.020–1.470). Multiple functional analyses including ALDH1A1 mRNA expression in blood cells of carriers, and reporters of EGFP and luciferase showed that the asYb8c4ins had a suppressive activity on gene transcription. Mechanistic explorations suggested that the asYb8c4ins induced no changes in CpG methylation and mRNA splicing of ALDH1A1 and appeared no binding of transcription factors. Conclusions Our results consolidate an involvement of ALDH1 in PD pathogenesis. The asYb8c4 polymorphism may be a functional output of its linkage disequilibrium-linked single nucleotide polymorphisms.

DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

“…The mechanism proposed in this study acquires significance if one considers its specificity for dopaminergic nigrostriatal neurons, at the early stages of PD neurodegeneration. The relevance of our results also hinge on epidemiological studies that correlated an increased risk of developing PD with the exposure to drugs, pesticides, and chemicals that act as ALDHs inhibitors 14 , 55 , enhanced by some genetic variations on Aldh1a1 and Aldh2 genes that were recently identified 14 , 80 , 81 . Unfortunately, only a few studies investigated the presence of DOPAL-modified αSyn species in PD autoptic samples, mostly because of the lack of reliable tools for their detection.…”

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

“…FASLG (Fas ligand) [574], GJC2 [575] and GJB1 [576] have been identified to be involved in the development of spasticity. CD24 [577], CD28 [578], HLA-DRB5 [579], LTF (lactotransferrin) [580], GPNMB (glycoprotein nmb) [581], TNFRSF9 [582], LRRC37A2 [583], DRD3 [584], CD163 [369], HGF (hepatocyte growth factor) [585], TRPM8 [446], TTR (transthyretin) [586], VEGFA (vascular endothelial growth factor A) [587], CHI3L1 [588], MAG (myelin associated glycoprotein) [589], SREBF1 [217], HIP1R [590], HK2 [591], GPR37 [592], NGFR (nerve growth factor receptor) [593], TF (transferrin) [594], HAPLN2 [451], MOG (myelin oligodendrocyte glycoprotein) [595], BIN1 [596], BMP2 [597], GADD45B [598], UNC5B [599], ADORA1 [600], SEPTIN4 [601], DHCR7 [602], SCD (stearoyl-CoA desaturase) [603], GIPC1 [604], ALDH1A1 [605] and CTNNA3 [606] participate in pathogenic processes of Parkinson’s disease. At present, investigation on these key regulatory genes and related molecular pathways is lacking.…”