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.     

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.     

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.     

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.     

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.     

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.     

Investigation of <Emphasis Type="Italic">TGFB2</Emphasis> as a candidate gene in multiple sclerosis and Parkinson’s disease

Given the known roles of TGFbeta2 in both regulating the immune system and promoting the survival of dopaminergic neurons, it is feasible that genetic variations in TGFB2 might play an aetiological role in neurological diseases such as Multiple Sclerosis (MS) and Parkinson's disease (PD). Hence we performed an indirect association analysis of TGFB2 using 8 haplotype-tagging SNPs in a population of 937 MS patients, 538 PD cases and 2022 controls. We found no evidence for association with susceptibility or progression of MS, but have demonstrated a trend towards association of the 5' region of the gene with susceptibility to PD. Further analysis of TGFB2 is warranted in other PD cohorts.     

Phenotype analysis in patients with early onset Parkinson’s disease with and without <Emphasis Type="Italic">parkin</Emphasis> mutations

The data regarding whether parkin genotype attributes phenotypic variation are conflicting. Since the incidence of parkin mutations is very low in patients with an age at onset (AAO) of >40 years, previous studies have unfairly compared phenotypes of two early onset Parkinson’s disease (EOPD) groups with different AAOs. Thus, we compared the clinical features between patients with and without parkin mutations in EOPD with an AAO of ≤40 years. Of the 124 patients with EOPD with an AAO of ≤40 years who were recruited and screened for parkin mutations, 84 completed assessments for comparison of the phenotype according to parkin genotype. Fourteen of the 84 subjects carried two parkin mutations; 6, a single mutation; and 64, no mutations. Patients with two mutations had significantly younger AAOs, longer duration of PD, and more common family history than patients without parkin mutations. Otherwise, motor and nonmotor symptoms did not differ between them. Subgroup analysis of EOPD with an AAO of ≤35 years revealed similar results. Phenotype of EOPD may depend on early AAOs rather than presence of parkin mutations.     

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.     

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.     

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.     

<Emphasis Type="Italic">hVMAT2</Emphasis>: A Target of Individualized Medication for Parkinson’s Disease

Vesicular monoamine transporter 2 (VMAT2) is responsible for sequestering cytosolically toxic dopamine into intracellular secretory vesicles. Animal genetic studies have suggested that reduced VMAT2 activity contributes to the genetic etiology of Parkinson’s disease (PD), but this role has not been established in humans. Based on human genetic association and meta-analysis, we first confirm the human VMAT2 (hVMAT2 or SLC18A2) promoter as a risk factor for PD in both family and unrelated US white people: marker rs363324 at –11.5 kb in the hVMAT2 promoter is reproducibly associated with PD in a cohort of nuclear families (p = 0.04506 in early-onset PD) and 3 unrelated US white people (meta-analysis p = 0.01879). In SH-SY5Y cells, low activity-associated hVMAT2 promoter confers high methylpiperidinopyrazole iodide cytotoxicity, which is likely attributed to functional polymorphisms bound by nuclear proteins. Interestingly, treatments with the dopamine neuron-protecting agent puerarin upregulates the promoter activity in a haplotype- and cell line-dependent manner. These pharmacogenetic findings suggest that hVMAT2 could be a risk factor and imply it as a target of genetic medications for PD.     

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     

Attenuation of β-Amyloid Toxicity <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> by Accelerated Aggregation

Accumulation and aggregation of β-amyloid (Aβ) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer’s disease. The self-assembled Aβ molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aβ toxicity is to facilitate the conversion of Aβ intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aβ by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aβ monomers, accompanying reduced Aβ cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aβ oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aβ aggregation-promotion effect can potentially be useful for developing strategies to reduce Aβ toxicity.     

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.     

<Emphasis Type="Italic">Folie à Deux</Emphasis> and shared psychotic disorder

Folie à deux (FAD) was first described in 19th century France. Since then, the concept has been elaborated, and several subtypes of FAD have been successively reported in France. In contrast, studies in German-speaking psychiatry mainly focused on the conceptual boundary between reactive/endogenous psychosis and etiological hypothesis (ie, psychogenesis vs genetic predisposition). In North America, Gralnick wrote a seminal review and redefined four subtypes of FAD by adopting the European classical concepts. More recently, "shared psychotic disorder" in DSM or "induced delusional disorder" in ICD-10 was branched off from FAD. However, several classical subcategories of FAD were not included in these recent definitions, the nosological significance of which should not be underestimated. We examined demographic data of FAD case reports published from the 19th to the 21st century and found that some of the earlier hypotheses, such as females being more susceptible, older and more intelligent individuals being more likely to be inducers, and sister-sister pairs being the most common relationship, were not supported. The controversial issue of the etiology of FAD-association of subjects or genetically driven psychosis-was re-examined in light of recent studies.     

A novel deletion in the <Emphasis Type="Italic">GJA12</Emphasis> gene causes Pelizaeus–Merzbacher-like disease

Pelizaeus–Merzbacher disease (PMD) and Pelizaeus–Merzbacher-like disease (PMLD) are hypomyelinating disorders of the central nervous system with a very similar phenotype. PMD is an X-linked disorder caused by mutations in PLP1. PMLD is an autosomal recessive condition caused by mutations in GJA12. We report a 5-year-old girl with a complex neurological syndrome and severe hypomyelination on brain magnetic resonance imaging. She harbored a homozygous 34-bp deletion in the coding region of GJA12. There are no distinctive features for the differential diagnosis of PMD/PMLD. GJA12 should be analyzed in all patients without PLP1 mutations but should also be considered the initial genetic test in women and in patients with consanguineous parents.     

The polynucleotide kinase 3′-phosphatase gene (<Emphasis Type="Italic">PNKP</Emphasis>) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to <Emphasis Type="Italic">MED25</Emphasis>

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3′-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.