Neurodegenerative disease and antioxidant biomarkers: A bidirectional Mendelian randomization study.

Objective: Previous observational studies have suggested that antioxidant imbalance is correlated with neurodegenerative diseases, while its cause-effect remains unclear. Thus, the goal of the present study is to explore the causal relationship between 11 antioxidant biomarkers and 3 most common neurodegenerative diseases [Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD)]. Methods: A bidirectional Mendelian randomization (MR) study was performed to investigate the causal effects by using 3 main methods (Variance Weighted (IVW), Weighted Median (WM), and MR-Egger regression) in the European population. The data of 11 antioxidant biomarkers were obtained from the open database by the most up-to-date Genome-Wide Association Studies (GWAS), the summary statistics of PD and ALS were obtained from the International Parkinson's Disease Genomics Consortium (IPDGC) (33,674 cases, and 449,056 controls), and the International Amyotrophic Lateral Sclerosis Genomics Consortium (IALSC) (20,806 cases and 59,804 controls), respectively. For AD, we specifically used two recently published GWAS data, one from the International Genomics of Alzheimer's Project (IGAP) (21,982 cases and 41,944 controls), and the other from a large meta-analysis (71,880 cases and 383,378 controls) as validation data. Results: Based on the Bonferroni correction p < 0.0015, there was no significant causal evidence for the antioxidant biomarkers on neurodegenerative diseases, however, the reverse analysis found that AD was significantly related to the decrease in retinol (IVW: beta = -0.023, p = 0.0007; WM: beta = -0.025, p = 0.0121), while the same analysis was carried out between the AD validation database and retinol, the results were consistent (IVW: beta = -0.064, p = 0.025). Moreover, AD on Glutathione S-transferase (GST), PD on Glutathione Peroxidase (GPX) as well as PD on uric acid (UA) also indicated potential causal-and-effect associations (IVW: p = 0.025; p = 0.027; p = 0.021, respectively). Conclusions: There was no sufficient evidence that antioxidant imbalance has a significant causal effect on neurodegenerative diseases. However, this study revealed that genetically predicted AD was significantly related to the decrease in retinol, which provides a new insight into previous research and indicates the possibility to regard retinol as potential biomarker for the diagnosis and progress of AD.

The Classification and Prediction of Ferroptosis-Related Genes in ALS: A Pilot Study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis, which is followed by degeneration of motor neurons in the motor cortex of the brainstem and spinal cord. The etiology of sporadic ALS (sALS) is still unknown, limiting the exploration of potential treatments. Ferroptosis is a new form of cell death and is reported to be closely associated with Alzheimer's disease (AD), Parkinson's disease (PD), and ALS. In this study, we used datasets (autopsy data and blood data) from Gene Expression Omnibus (GEO) to explore the role of ferroptosis and ferroptosis-related gene (FRG) alterations in ALS. Gene set enrichment analysis (GSEA) found that the activated ferroptosis pathway displayed a higher enrichment score, and the expression of 26 ferroptosis genes showed obvious group differences between ALS and controls. Using weighted gene correlation network analysis (WGCNA), we identified FRGs associated with ALS, of which the Gene Ontology (GO) analysis displayed that the biological process of oxidative stress was the most to be involved in. KEGG pathway analysis revealed that the FRGs were enriched not only in ferroptosis pathways but also in autophagy, FoxO, and mTOR signaling pathways. Twenty-one FRGs (NR4A1, CYBB, DRD4, SETD1B, LAMP2, ACSL4, MYB, PROM2, CHMP5, ULK1, AKR1C2, TGFBR1, TMBIM4, MLLT1, PSAT1, HIF1A, LINC00336, AMN, SLC38A1, CISD1, and GABARAPL2) in the autopsy data and 16 FRGs (NR4A1, DRD4, SETD1B, MYB, PROM2, CHMP5, ULK1, AKR1C2, TGFBR1, TMBIM4, MLLT1, HIF1A, LINC00336, IL33, SLC38A1, and CISD1) in the blood data were identified as target genes by least absolute shrinkage and selection operator analysis (LASSO), in which gene signature could differentiate ALS patients from controls. Finally, the higher the expression of CHMP5 and SLC38A1 in whole blood, the shorter the lifespan of ALS patients will be. In summary, our study presents potential biomarkers for the diagnosis and prognosis of ALS.

Clinical manifestations and acid alpha-glucosidase mutation characterisation of a cohort of patients with late-onset Pompe disease in eastern China.

BACKGROUND: Pompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase (GAA) gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy. METHODS: Fourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the GAA gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL. RESULTS: The study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median diagnostic delay from onset was 3.0 years (0-22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78). CONCLUSIONS: The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.