No Association of <Emphasis Type="Italic">LOXL1</Emphasis> Gene Polymorphisms with Alzheimer’s Disease

Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer’s disease (AD). Although several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE ε4 genotype and to CSF (T-tau, P-tau, and Aβ_1–42). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found. These results do not support LOXL1 as being a major risk gene for AD.     

Genetic Analysis of <Emphasis Type="Italic">FBXO2</Emphasis>, <Emphasis Type="Italic">FBXO6</Emphasis>, <Emphasis Type="Italic">FBXO12</Emphasis>, and <Emphasis Type="Italic">FBXO41</Emphasis> Variants in Han Chinese Patients with Sporadic Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690–0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD.     

Oxidative Stress and <Emphasis Type="Italic">β</Emphasis>-Amyloid Protein in Alzheimer’s Disease

Oxidative stress has been proposed to be an important factor in the pathogenesis of Alzheimer’s disease (AD) and contributed to β-amyloid (Aβ) generation. Interaction between oxidative stress and neuro-inflammation leads to Aβ generation. AD is associated with an increase in blood–brain barrier (BBB) permeability due to tight junction involvement. Oxidative stress decreases the expression of low-density lipoprotein receptor-related protein 1 and up-regulates receptor for advanced glycation end products in BBB and increases the BBB permeability, which could potentially lead to increased deposition of Aβ within AD brain. Apoptosis takes place in the pathogenesis of AD, and oxidative stress contributes to apoptosis through both extrinsic pathway and intrinsic pathway. Oxidative stress-induced apoptosis may be a potential factor to Aβ generation. Aβ generation requires two sequential cleavages of APP, with the two proteolytic enzymes: β-secretase and γ-secretase. Oxidative damage up-regulates Aβ via inducing activity of β- and γ-secretases. In this review, we will focus on the mechanism and pathway that oxidative stress contributes to Aβ generation.     

Alzheimer’s Disease Risk Variant rs2373115 Regulates <Emphasis Type="Italic">GAB2</Emphasis> and <Emphasis Type="Italic">NARS2</Emphasis> Expression in Human Brain Tissues

Genetic association studies have identified significant association between the GAB2 rs2373115 variant and Alzheimer’s disease (AD). However, it is unknown whether rs2373115 affects the regulation of nearby genes. Here, we evaluate the potential effect of rs2373115 on gene expression using multiple eQTL (expression quantitative trait loci) datasets from human brain tissues from the Mayo Clinic brain expression genome-wide association study (eGWAS), the UK Brain Expression Consortium (UKBEC), the Genotype-Tissue Expression (GTEx) project, and the Brain xQTL Serve. Our findings indicate that the rs2373115 C allele is associated with increased NARS2 expression, and both reduced and increased GAB2 expression in human tissues. Using a large-scale AD case-control expression dataset, we found increased GAB2 expression and reduced NARS2 expression in AD cases compared with controls. We believe that our findings provide important information regarding the rs2373115 variant and expression of nearby genes with respect to AD risk.     

The analysis of association between <Emphasis Type="Italic">SNCA</Emphasis>, <Emphasis Type="Italic">HUSEYO</Emphasis> and <Emphasis Type="Italic">CSMD1</Emphasis> gene variants and Parkinson’s disease in Iranian population

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. Both genetic and environmental factors are involved in the etiology of the disease. Many studies have revealed the susceptibility genes and variations for PD which need further confirmation. Here we evaluated the association of variations in SNCA, HUSEYO and CSMD1 genes with PD. A case–control study was conducted with 489 PD patients and 489 healthy controls. DNA was extracted from peripheral blood of all subjects and rs356220 and rs11931074 in SNCA, rs2338971 in HUSEYO and rs12681349 in CSMD1 were genotyped using PCR–RFLP method. The genotypes and allele frequencies were significantly different between case and control groups for rs356220, rs11931074 and rs2338971 but not for rs12681349. We provided further evidence that rs356220 is associated with increased risk of PD supporting previous studies in Caucasian-based and Japanese populations. The association of rs11931074 with decreased risk of PD was also significant. This study revealed the first evidence of the association of rs2338971 with increased risk of PD in the Iranian population. Nevertheless, these findings need further validation via more replication studies.     

Genetic variability in <Emphasis Type="Italic">SNCA</Emphasis> and Parkinson’s disease

Over the last decades, increasing knowledge about the genetic architecture of Parkinson’s disease has provided novel insights into the pathogenesis of the disorder, generating hypotheses for further research. Characterizing the role of SNCA, encoding the α-synuclein protein, has been a particularly important aspect of this development. The identification of SNCA as the first gene implicated in monogenic parkinsonism led to the recognition of α-synuclein as a key protein in the pathogenesis and a major component of pathological hallmark lesions. An association between common variants in SNCA and risk of sporadic Parkinson’s disease has been established through numerous studies. We review our current understanding of SNCA variability contributing to Parkinson’s disease, highlighting the characterization of functionally relevant susceptibility alleles as a major future challenge. We argue that new strategies will be needed to pinpoint the variants that are ultimately responsible for the signals detected in association studies, where targeted resequencing may represent an attractive initial approach.     

Amyloid Precursor Protein Gene (<Emphasis Type="Italic">APP</Emphasis>) Variation in Late-Onset Alzheimer’s Disease

Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer’s disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.     

Broadening the phenotype of <Emphasis Type="Italic">TARDBP</Emphasis> mutations: the <Emphasis Type="Italic">TARDBP</Emphasis> Ala382Thr mutation and Parkinson’s disease in Sardinia

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.     

Genetic analysis of <Emphasis Type="Italic">heme oxygenase</Emphasis>-<Emphasis Type="Italic">1</Emphasis> (<Emphasis Type="Italic">HO-1</Emphasis>) in German Parkinson’s disease patients

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic inclusions (Lewy bodies). Iron, which is elevated in the substantia nigra (SN) of PD patients, seems to be of pivotal importance, because of its capacity to enhance the amplification of reactive-oxygen species. Therefore, it is tempting that the iron-releasing key enzyme in heme catabolism, heme oxygenase-1 (HO-1), may represent a candidate for a genetic susceptibility to PD. In the current study, we examined a (GT)n fragment length polymorphism in the promoter region, as well as three coding SNPs in the HO-1 gene in order to assess if certain genotypes are associated with PD. Furthermore, peripheral blood expression levels of HO-1 in PD patients and healthy probands were compared. However, our analyses did not reveal a significant association of these genetic markers in the HO-1 gene with an increased susceptibility to PD.     

No Association of <Emphasis Type=Italic>VEGF</Emphasis> Polymorphims with Alzheimer’s Disease

The vascular hypothesis of Alzheimer’s disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [−2578]) and rs1570360 [−1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE ε4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and β₄₂-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.     

Unraveling the Role of Metal Ions and Low Catalytic Activity of Cytochrome <Emphasis Type="Italic">C</Emphasis> Oxidase in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by high levels of aluminum and certain other metal ions in the brain: The disease is also characterized by low activity of brain cytochrome c oxidase (COX) but whether the elevated metal ions and the low COX activity are linked is not known. Moreover, COX is known to exhibit two catalytic rates (V _max) and two substrate binding constants (K _m) but it is not known which of these is affected in AD. In this study, we employed the Klatzo AD rabbit model to evaluate the impact of elevated metal ions on brain COX activity. New Zealand white rabbits were injected intra-cerebrally with 1.4% solutions of either AlCl₃, FeCl₃, CaCl₂, or MgCl₂; and 10 days, later the brain mitochondria were isolated. Polarographic assay revealed that compared to the controls, all four metals led to decreases in the V _max of the enzyme’s low affinity site. The respective decreases were; 16%, 36%, 18%, and 30%. The results suggest a sequence of events in vivo in which oxygen radical damage to mitochondria and COX leads to low ATP production and excess heme establishing conditions thought to be ideal for neurodegeneration.     

Association between <Emphasis Type="Italic">FGF20 rs12720208</Emphasis> gene polymorphism and Parkinson’s disease: a meta-analysis

Previous studies have claimed the association of rs12720208 polymorphism in the fibroblast growth factor 20 (FGF20) gene with the increased risk of Parkinson’s disease (PD), but results from the published data were controversial. The aim of our present meta-analysis was to estimate the overall association between FGF20 rs12720208 polymorphism and the risk of PD. Case–control studies with sufficient data evaluating the association between rs12720208 C/T polymorphism and PD susceptibility were systematically identified in PubMed, OVID, SinoMed, Chinese National Knowledge Infrastructure (CNKI) up to July 10, 2015. A total of 3402 PD patients and 3739 controls from seven case–control studies were collected for this meta-analysis. The pooled odds ratio (OR) with its 95 % confidence interval (CI) was calculated to assess the genetic association between FGF20 rs12720208 polymorphism and the risk of PD. In this study, no enough proof was found to prove the association in any genetic models with random-effects model (CT+TT vs. CC: OR = 1.147, 95 % CI: 0.883–1.489, P = 0.304; TT vs. CC+CT: OR = 1.754, 95 % CI: 0.878–3.505, P = 0.112; T vs. C: OR = 1.169, 95 % CI = 0.919–1.487, P = 0.204; TT+CC vs. CT: OR = 0.906, 95 % CI = 0.694–1.182, P = 0.466). Our results suggest that there is no sufficient evidence to support the association between rs12720208 polymorphism and PD risk. Studies with larger sample size across diverse populations and subgroup analyses are necessary in the future.     

Expression analysis of <Emphasis Type="Italic">GRIN2B</Emphasis>, <Emphasis Type="Italic">BDNF</Emphasis>, and <Emphasis Type="Italic">IL-1β</Emphasis> genes in the whole blood of epileptic patients

Epilepsy is a brain disorder with a global prevalence of 1%. It has been attributed to genetics and environmental factors. Despite efforts to identify the molecular pathology of epilepsy, the underlying mechanism is not understood yet. This study was carried out to compare GRIN2B, BDNF, and IL-1β gene expressions in 50 patients suffering from generalized epilepsy with tonic-colonic seizures and 50 age- and sex-matched healthy subjects using TaqMan Real-time PCR. Our results demonstrated significant upregulation of these genes in people with epilepsy compared with healthy subjects. We also found a positive correlation between GRIN2B and BDNF expression (r²=0.4619, p?<?0.0001), BDNF and IL-1β expression (r²?=?0.515, p?<?0.0001), and GRIN2B and IL-1β gene expressions (r²?=?0.666, p?<?0.0001) which implies the possibility to estimate the expression level of these genes by assessment of expression of one of them. Considering the results of the previous animal studies which showed upregulation of these genes in brain tissues of epileptic animals, the expression levels of GRIN2B, BDNF, and IL-1β in blood samples might be related to their expression in brain samples. Future studies are needed to assess the role of these genes in the pathogenesis of epilepsy and evaluate whether altered expression of these genes along with imaging methods can facilitate subtyping the epilepsy.     

Influence of four polymorphisms in <Emphasis Type="Italic">ABCA1</Emphasis> and <Emphasis Type="Italic">PTGS2</Emphasis> genes on risk of Alzheimer’s disease: a meta-analysis

We preformed this meta-analysis to investigate the influence of ABCA1 (ATP-binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G-765C) polymorphisms on the risk of Alzheimer’s disease (AD). Seventeen eligible case–control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR = 1.12, 95 % CI: 1.01–1.24; homozygous TT vs CC: OR = 1.26, 95 % CI: 1.03–1.55; and recessive TT vs TC + CC: OR = 1.33, 95 % CI: 1.12–1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-ε4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P < 0.0001 in five genetic models (e.g., allelic C vs G: OR = 0.59, 95 % CI: 0.50–0.70; homozygous CC vs GG: OR = 0.31, 95 % CI: 0.18–0.52; and heterozygous CG vs GG: OR = 0.64, 95 % CI: 0.52–0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-ε4.     

Lower functional connectivity of default mode network in cognitively normal young adults with mutation of <Emphasis Type="Italic">APP</Emphasis>, <Emphasis Type="Italic">presenilins</Emphasis> and <Emphasis Type="Italic">APOE ε4</Emphasis>

In this study, we used resting-state functional magnetic resonance imaging to explore the genetic effects of amyloid precursor protein (APP) or presenilins mutation and apolipoprotein E (APOE) ε4 on the default-mode network (DMN) in cognitively intact young adults (24.1 ± 2.5 years). Both the APP or presenilin-1/2 group and the APOE ε4 group had significantly lower DMN functional connectivity (FC) in the some brain regions like precuneus/middle cingulate cortices (PCu/MCC) than controls (AlphaSim corrected, P < 0.05). Only a lower FC tendency was demonstrated (control < APOE ε4 < APP or presenilin-1/2 group). Moreover, lower FC in PCu/MCC is correlated with some neuropsychological assessments such as similarity test in APOE ε4 group. These findings indicate that DMN FC alteration in APP or presenilin-1/2 or APOE ε4 subjects is prior to the occurrence of neurological alterations and clinical symptoms, and DMN FC might be a valuable biomarker to detect genetic risk in the preclinical stage.     

The murine <Emphasis Type="Italic">Bis1</Emphasis> seizure gene and the <Emphasis Type="Italic">Kcnab2</Emphasis> gene encoding the β2-subunit of the K<Superscript>+</Superscript> channel are different

Received: April 22, 1999 / Accepted: August 30, 1999 / Published online: January 10, 2000     

Genetic association study between <Emphasis Type="Italic">RIT2</Emphasis> and Parkinson’s disease in a Han Chinese population

Recent several meta-analyses and certain case–control studies suggested that the Ras-like without CAAX 2 (RIT2) rs12456492 increased the risk of Parkinson’s disease (PD) in Asian and Caucasian populations. However, as so far, the association between RIT2 rs12456492 and PD is still controversial. We investigated genetic association of RIT2 rs12456492 with PD susceptibility in a Han Chinese population of 1747 ethnic Han Chinese subjects comprising 884 PD patients and 863 healthy controls. The minor allele frequency (MAF) of G at the RIT2 rs12456492 was not significantly different between the cases and the controls. Furthermore, no significant differences were observed in genotype distribution between PD patients and healthy controls for the RIT2 rs12456492, even after being stratified by age at onset and gender. In addition, we found that no significant differences were detected in the clinical manifestations for gender, age at onset, and onset symptoms between PD patients with AG + GG genotypes and those with AA genotypes. Our study from the mainland China demonstrates that RIT2 rs12456492 do not increase the risk of developing PD. Therefore, more replication studies in additional Chinese population and other cohorts are warranted to further clarify the role of RIT2 rs12456492 in PD susceptibility.     

Olfactory Dysfunction in Parkinson’s Disease Patients with the <Emphasis Type="Italic">LRRK2</Emphasis> G2385R Variant

Olfactory dysfunction has been reported in Parkinson’s disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The “five-odor olfactory detection array”, an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without (iPD) and 25 with (LRRK2-PD) the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.