Genetics variants and expression of the SCARB2 gene in the pathogenesis of Parkinson's disease in Russia

Usenko, Tatiana; Bezrukova, Anastasia; Bogdanova, D.; Kopytova, Alena E.; Senkevich, Konstantin; Gracheva, E.; Timofeeva, A. A.; Miliukhina, Irina; Zakharova, Ekaterina; Anton, Emil; Pchelina, Sofya

doi:10.1016/j.neulet.2020.135509

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…SCARB2 gene encodes to lysosomal integral membrane protein 2 (LIMP2), a protein responsible for transporting β-GCase from the ER to the lysosome through interaction with mannose-6-phosphate receptor [88,173]. Different genetic studies have determined the implication of mutations in this gene in the development of PD [174][175][176][177][178]. Moreover, overexpression of α-syn in ASO Tg/Tg mouse models showed reduced levels of mannose-6-phosphate receptor type I (also known as MPR300) [179].…”

Section: Scarb2mentioning

confidence: 99%

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

et al. 2021

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Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.

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Section: Scarb2mentioning

confidence: 99%

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

et al. 2021

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“…This is supported by the fact that the LIMP‐2‐coding SCARB2 gene is itself a risk factor for PD, connected via GCase and the GluCer/a‐syn axis. [ 41 , 53 , 54 ] We therefore investigated whether the three common GCase variants E326K, N370S and L444P exhibited altered binding to LIMP‐2. Overexpression of FL‐LIMP‐2 along GCase variants in HEK293T cells led to increased protein levels of wt, E326K, and N370S in LE fractions (Figure 1D,E ), suggesting interaction with LIMP‐2 and transport of these variants.…”

Section: Discussionmentioning

confidence: 99%

Activation and Purification of ß‐Glucocerebrosidase by Exploiting its Transporter LIMP‐2 – Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease

Dobert,

Bub,

Mächtel

et al. 2024

Advanced Science

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Genetic variants of GBA1 can cause the lysosomal storage disorder Gaucher disease and are among the highest genetic risk factors for Parkinson's disease (PD). GBA1 encodes the lysosomal enzyme beta‐glucocerebrosidase (GCase), which orchestrates the degradation of glucosylceramide (GluCer) in the lysosome. Recent studies have shown that GluCer accelerates α‐synuclein aggregation, exposing GCase deficiency as a major risk factor in PD pathology and as a promising target for treatment. This study investigates the interaction of GCase and three disease‐associated variants (p.E326K, p.N370S, p.L444P) with their transporter, the lysosomal integral membrane protein 2 (LIMP‐2). Overexpression of LIMP‐2 in HEK 293T cells boosts lysosomal abundance of wt, E326K, and N370S GCase and increases/rescues enzymatic activity of the wt and E326K variant. Using a novel purification approach, co‐purification of untagged wt, E326K, and N370S GCase in complex with His‐tagged LIMP‐2 from cell supernatant of HEK 293F cells is achieved, confirming functional binding and trafficking for these variants. Furthermore, a single helix in the LIMP‐2 ectodomain is exploited to design a lysosome‐targeted peptide that enhances lysosomal GCase activity in PD patient‐derived and control fibroblasts. These findings reveal LIMP‐2 as an allosteric activator of GCase, suggesting a possible therapeutic potential of targeting this interaction.

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“…It is a type of specific glucose cerebral fat enzyme combined with ligands, involved in the lysosomal pathway. The related research fields are mostly Parkinson's disease with abnormal lysosomal metabolism [ 22 , 23 ], Gaucher’s disease and myoclonic epilepsy [ 24 , 25 ]. Yamayoshi et al [ 12 , 13 ] found that the tissue distribution of EV-71 virus antigen was well correlated with SCARB2, and further found that this receptor was involved in the endocytosis and membrane transport of pathogenic bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…Ting-Yu Yen studied the relationship between SCARB2, PSGL-1, ANXA2 polymorphisms and clinical severity, and found that rs11097262 was associated with rs6824953 located in the intron region of SCARB2 gene, considering that it may regulate the function or expression of SCARB2 and thus affect the susceptibility to EV-71 [ 32 ]. In this study, 14 introns were selected: rs121909119, rs727502772, rs727502781, rs886041074, and rs886041076 were considered to be the sites with pathological clinical significance on NCBI website; rs6812193 is a hot spot site that can be found in the literatures [ 23 , 37 – 39 ]; rs1470194, rs2119733, rs2869851, rs57374265, rs6824953, rs72857048, rs75285019, and rs7697073 are the TAGSNP sites. Among these introns of this study, rs72857048 is not in CHB; rs2869851 is not detected; rs121909119, rs727502772, rs727502781, rs886041074, and rs886041076 are not in line with MAF value.…”

Section: Discussionmentioning

confidence: 99%

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Relationship between polymorphism of receptor SCARB2 gene and clinical severity of enterovirus-71 associated hand-foot-mouth disease

Wang

Liu

et al. 2021

Virol J

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Background To investigate the relationship between polymorphism of scavenger receptor class B member 2 (SCARB2) gene and clinical severity of enterovirus (EV)-71 associated hand-foot-mouth disease (HFMD). Methods Among the 100 recruited cases, 56 were in the severe HFMD group (case group) and 44 were in the general HFMD group (control group). By screening functional single nucleotide polymorphisms (SNPs) and hot SNPs, and performing SNP site optimization, some SNP sites of SCARB2 gene were selected for analysis. Genotyping was performed using a MassArray platform. PLINK software was used for statistical processing and analysis of the correlation differences between the mutant genotypes in the severe and general HFMD groups. The relationship between the SNPs and clinical severity of enterovirus (EV)-71 associated HFMD was assessed. Results 28 SNPs in SCARB2 were selected by site optimization. Then three loci were not in agreement with the minor allele frequency (MAF) in the 1000 Han Chinese in Beijing (CHB) dataset. Another three loci could not be detected. Nine loci were not suitable for further analysis (MAF < 0.01 and Hardy–Weinberg [HWE] P < 0.001). A total of 13 sites were subsequently analyzed. Through Fisher analysis, the frequency of the rs6812193 T allele was 0.134 and 0.034 in the severe and general HFMD groups, respectively (P 0.023 < 0.05, odds ratio [OR] 4.381 > 1). Logistic regression analysis of rs6812193 T alleles between the severe and general HFMD groups, respectively (P 0.023 < 0.05, OR 4.412 > 1, L95 1.210 > 1). Genotype logistic regression analysis of the rs6812193 alleles CT + TT versus CC gave an OR of 4.56 (95% confidence interval [95% CI] 1.22–17.04, P = 0.012). Conclusion The rs6812193 T allele was a susceptibility SNP for SHFMD, and the rs6812193 polymorphism might be significantly associated with the susceptibility to EV-71 infection.

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Genetics variants and expression of the SCARB2 gene in the pathogenesis of Parkinson's disease in Russia

Cited by 7 publications

References 18 publications

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Activation and Purification of ß‐Glucocerebrosidase by Exploiting its Transporter LIMP‐2 – Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease

Relationship between polymorphism of receptor SCARB2 gene and clinical severity of enterovirus-71 associated hand-foot-mouth disease

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