Roles of Post-translational Modifications in Spinocerebellar Ataxias

Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, etc., of proteins can modulate protein properties such as intracellular distribution, activity, stability, aggregation, and interactions. Therefore, PTMs are vital regulatory mechanisms for multiple cellular processes. Spinocerebellar ataxias (SCAs) are hereditary, heterogeneous, neurodegenerative diseases for which the primary manifestation involves ataxia. Because the pathogenesis of most SCAs is correlated with mutant proteins directly or indirectly, the PTMs of disease-related proteins might functionally affect SCA development and represent potential therapeutic interventions. Here, we review multiple PTMs related to disease-causing proteins in SCAs pathogenesis and their effects. Furthermore, we discuss these PTMs as potential targets for treating SCAs and describe translational therapies targeting PTMs that have been published

A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

Background: Various studies have reported associations between synuclein alpha (SNCA) polymorphisms and Parkinson's disease (PD) risk. However, the results are inconsistent. We conducted a comprehensive meta-analysis of the associations between SNCA single-nucleotide polymorphisms (SNPs) and PD risk in overall populations and subpopulations by ethnicity.Methods: Standard meta-analysis was conducted according to our protocol with a cutoff point of p < 0.05. To find the most relevant SNCA SNPs, we used a cutoff point of p < 1 × 10−5 in an analysis based on the allele model. In the subgroup analysis by ethnicity, we divided the overall populations into five ethnic groups. We conducted further analysis on the most relevant SNPs using dominant and recessive models to identify the contributions of heterozygotes and homozygotes regarding each SNP.Results: In our comprehensive meta-analysis, 24,075 cases and 22,877 controls from 36 articles were included. We included 16 variants in the meta-analysis and found 12 statistically significant variants with p < 0.05. After narrowing down the variants using the p < 1 × 10−5 cutoff, in overall populations, seven SNPs increased the risk of PD (rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029, with odds ratios [ORs] of 1.22–1.38) and one SNP decreased the risk (rs356186, with an OR of 0.77). In the East Asian group, rs2736990 and rs11931074 increased the risk (with ORs of 1.22–1.34). In the European group, five SNPs increased the risk (rs356219, rs181489, rs2737029, rs356165, and rs11931074, with ORs of 1.26–1.37) while one SNP decreased the risk (rs356186, with an OR of 0.77). The heterozygotes and homozygotes contributed differently depending on the variant.Conclusions: In summary, we found eight SNCA SNPs associated with PD risk, which had obvious differences between ethnicities. Seven SNPs increased the risk of PD and one SNP decreased the risk in the overall populations. In the East Asian group, rs2736990 and rs11931074 increased the risk. In the European group, rs356219, rs181489, rs2737029, rs356165, and rs11931074 increased the risk while rs356186 decreased the risk. Variants with the highest ORs and allele frequencies in our analysis should be given priority when carrying out genetic screening

The Effects of SNCA rs894278 on Resting-State Brain Activity in Parkinson’s Disease

The pathogenesis of Parkinson’s disease (PD) is not well established. The rs894278 polymorphism of SNCA has been associated with PD. We performed this study to investigate the relationship between rs894278 and PD status on resting-state brain activity, by analyzing the amplitude of low-frequency fluctuation (ALFF). A total of 81 PD patients and 64 healthy controls were recruited. Disease severity and PD stage were evaluated in PD patients using the unified Parkinson’s disease rating scale (UPDRS) and the Hoehn and Yahr (HY) scale, while the cognitive function of all participants was assessed using the mini-mental state examination (MMSE). All participants were genotyped for the rs894278 SNP and underwent a resting state functional magnetic resonance imaging scan. We found that the ALFF values of PD patients in the lingual gyrus and left caudate were lower than those of HCs; and the ALFF values for the right fusiform of participants with G allele were lower than those of participants without G allele. And we further revealed higher ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the PD group and lower ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the HC group. Our findings show that rs894278 and PD status interactively affect the brain activity of PD patients and HCs, and changes in the brain connectomes may play a key role in the pathogenesis of PD. Thus, our work sheds light on the mechanism underlying PD pathogenesis

A Comprehensive Analysis of Population Differences in LRRK2 Variant Distribution in Parkinson's Disease

Background:LRRK2 variants have been demonstrated to have distinct distributions in different populations. However, researchers have thus far chosen to focus on relatively few variants, such as R1628P, G2019S, and G2385R. We therefore investigated the relationship between common LRRK2 variants and PD risk in various populations.Methods: Using a set of strict inclusion criteria, six databases were searched, resulting in the selection of 94 articles covering 49,299 cases and 47,319 controls for final pooled analysis and frequency analysis. Subgroup analysis were done for Africans, European/West Asians, Hispanics, East Asians, and mixed populations. Statistical analysis was carried out using the Mantel-Haenszel approach to determine the relationship between common LRRK2 variants and PD risk, with the significance level set at p < 0.05.Results: In the absence of obvious heterogeneities and publication biases among the included studies, we concluded that A419V, R1441C/G/H, R1628P, G2019S, and G2385R were associated with increased PD risk (p: 0.001, 0.0004, < 0.00001, < 0.00001, and < 0.00001, respectively), while R1398H was associated with decreased risk (p: < 0.00001). In East Asian populations, A419V, R1628P, and G2385R increased risk (p: 0.001, < 0.00001, < 0.00001), while R1398H had the opposite effect (p: 0.0005). G2019S increased PD risk in both European/West Asian and mixed populations (p: < 0.00001, < 0.00001), while R1441C/G/H increased risk in European/West Asian populations only (p: 0.0004).Conclusions: We demonstrated that LRRK2 variant distribution is different among various populations, which should inform decisions regarding the development of future genetic screening strategies

Multiple Visual Rating Scales Based on Structural MRI and a Novel Prediction Model Combining Visual Rating Scales and Age Stratification in the Diagnosis of Alzheimer's Disease in the Chinese Population

Objective: To explore the value of multiple visual rating scales based on structural MRI in the diagnosis of Alzheimer's disease (AD) in the Chinese population.Materials and Methods: One hundred patients with AD and 100 age- and gender- matched cognitively normal controls were enrolled in this study. All the participants underwent neuropsychological tests and a structural MRI scan of the brain, among them, 42 AD cases and 47 cognitively normal controls also underwent 3D-T1 weighted sequence used for the analysis of voxel-based morphometry (VBM). The AD cases were divided into mild and moderate–severe groups according to the mini-mental state examination. Each participant was evaluated by two trained radiologists who were blind to the clinical information, according to the six visual rating scales, including for medial temporal lobe atrophy (MTA), posterior atrophy (PA), anterior temporal (AT), orbitofrontal (OF) cortex, anterior cingulate (AC), and fronto-insula (FI). Finally, we estimated the relationship between the visual rating scales and the volume of corresponding brain regions, using correlation analysis, and evaluated the specificity and sensitivity of every single scale and combination of multiple scales in the diagnosis of AD, using a receiver operating characteristic (ROC) curve and establishing a logistic regression model.Results: The optimal cutoff of all six visual rating scales for distinguishing AD cases from normal controls was 1.5. Using automated classification based on all six rating scales, the accuracy for distinguishing AD cases from healthy controls ranged from 0.68 to 0.80 (for mild AD) and 0.77–0.90 (for moderate–severe AD), respectively. A diagnostic prediction model with a combination of MTA and OF results was made as follows: Score = BMTA(score) + BOF(score) −1.58 (age < 65 years); Score = BMTA(score) + BOF(score) −4.09 (age ≥65 years). The model was superior to any single visual rating scale in the diagnosis of mild AD (P < 0.05).Conclusion: Each of the six visual rating scales could be applied to the diagnosis of moderate-severe AD alone in the Chinese population. A prediction model of the combined usage of MTA, OF, and age stratification for the early diagnosis of AD was preliminarily established

Identifying SYNE1 Ataxia With Novel Mutations in a Chinese Population

Objective: Variants in SYNE1 have been widely reported in ataxia patients in Europe, with highly variable clinical phenotype. Until now, no mutation of SYNE1 ataxia has been reported among the Chinese population. Our aim was to screen for SYNE1 ataxia patients in China and extend the clinicogenetic spectrum.Methods: Variants in SYNE1 were detected by high-throughput sequencing on a cohort of 126 unrelated index patients with unexplained autosomal recessive or sporadic ataxia. Pathogenicity assessments of SYNE1 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. Clinical assessments were conducted by two experienced neurologists.Results: Two Chinese families with variable ataxia syndrome were identified (accounting for 1.6%; 2/126), separately caused by the novel homozygous SYNE1 mutation (NM_033071.3: c.21568C>T, p.Arg7190Ter), and compound heterozygous SYNE1 mutation (NM_033071.3: c.18684G>A, p.Trp6228Ter; c.17944C>T, p.Arg5982Ter), characterized by motor neuron impairment, mental retardation and arthrogryposis.Conclusions:SYNE1 ataxia exists in the Chinese population, as a rare form of autosomal recessive ataxia, with a complex phenotype. Our findings expanded the ethnic, phenotypic and genetic diversity of SYNE1 ataxia

Is the High Frequency of Machado-Joseph Disease in China Due to New Mutational Origins?

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1–5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country. We analyzed 50 families with MJD patients in two or more generations to study the hypothesis that new mutational events have occurred in this population. Haplotypes based on 20 SNPs have shown new genetic backgrounds segregating with MJD mutations in our cohort from China. We found the “Joseph-derived” lineage (Joseph lineage with a G variant in rs56268847) to be very common among Chinese MJD patients. Moreover, we estimated the time for the origin of this MJD SNP background based on STR diversity flanking the (CAG)n of ATXN3. It was surprising to find that the Chinese MJD population originated from 8,000 to 17,000 years ago, far earlier than the previous literature reports, which will be an important evidence to explain the origin, spread and founder effects of MJD

Recent Advances in Biomarkers for Parkinson’s Disease

Parkinson’s disease (PD) is one of the common progressive neurodegenerative disorders with several motor and non-motor symptoms. Most of the motor symptoms may appear at a late stage where most of the dopaminergic neurons have been already damaged. In order to provide better clinical intervention and treatment at the onset of disease, it is imperative to find accurate biomarkers for early diagnosis, including prodromal diagnosis and preclinical diagnosis. At the same time, these reliable biomarkers can also be utilized to monitor the progress of the disease. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine

The association between Parkinson’s disease and autoimmune diseases: A systematic review and meta-analysis

Parkinson’s disease (PD) is a neurodegenerative disorder that frequently occurs in the older population. Previous epidemiological studies have suggested an association between PD and autoimmune diseases (AIDs). However, some studies have shown conflicting results. This study aimed to summarize existing epidemiological studies on the association between PD with AIDs and to conduct a meta-analysis of combinable results. Four electronic databases (PubMed, Embase, Web of Science Core Collection, and MEDLINE) were searched from each database’s inception date until December 12, 2022. All studies that explored the relationship between PD and AIDs were included for quantitative analysis and qualitative review. The pooled relative risk with 95% confidence intervals (CIs) was calculated using a random or fixed effects model. A total of 46 observational studies involving 873,643 patients and 13,402,821 controls were included; ultimately, 38 studies were included in the meta-analysis. The risk of PD combined with AIDs was significantly higher (odds ratio [OR]=1.55, 95% CI: 1.33–1.81), and subgroup analysis found no significant differences in risk by study type, gender, age, and race. Regarding the AID types, the results showed an increased risk of PD combined with bullous pemphigoid (OR=2.67, 95% CI: 2.15–3.31), inflammatory bowel disease (OR=1.30, 95% CI: 1.18–1.45), Crohn’s disease (OR=1.30, 95% CI: 1.20–1.42), ulcerative colitis (OR=1.31, 95% CI: 1.14–1.50), Sjögren’s syndrome (OR=1.61, 95% CI: 1.24–2.09), and Graves’ disease (OR=1.45, 95% CI: 1.24–1.70) than controls. However, there appeared to be no significant association between PD and systemic lupus erythematosus (OR=0.82, 95% CI: 0.66–1.03), multiple sclerosis (OR=2.02, 95% CI: 0.87–4.70), rheumatoid arthritis (OR=0.79, 95% CI: 0.61–1.03), or celiac disease (OR=1.16, 95% CI: 0.79–1.69). This study supports the existence of a strong link between AIDs and PD. When PD and AIDs are identified, clinicians need to be aware of the possibility of coexistence. However, there are some limitations of this study, such as the apparent heterogeneity of some of the results and the fact that most of the included study types were retrospective. Therefore, future larger prospective cohort studies are needed to further explore the interaction between PD and AIDs.Systematic review registrationINPLASY, identifier INPLASY202280088

Factors Associated With Dyskinesia in Parkinson's Disease in Mainland China

Background and Objectives: Studies examining the risk factors for dyskinesia in Parkinson's disease (PD) have been inconsistent, and racial differences exist. Since there have been no systematic studies of the characteristics of dyskinesia in the Mainland Chinese population, we sought to elucidate the risk factors for dyskinesia.Methods: A total of 1974 PD patients from Mainland China were systematically investigated by univariable and multivariable analyses. PD patients with and without dyskinesia were stratified into 4 groups according to levodopa equivalent daily dose (LEDD) and analyzed by a Cox proportional hazards model. A longitudinal study of 87 patients with dyskinesia was classified into 3 groups according to the duration from onset of PD to the initiation of levodopa, and comparisons among groups were analyzed by the Mann-Whitney test.Results: Early age of onset, long disease duration, being female, high LEDD, low UPDRS III scores (ON-state) and high Hoehn-Yahr stage (ON-state) were predictors of dyskinesia. Dyskinesia was levodopa dosage-dependent, and the incidence increased remarkably when LEDD exceeded 300 mg/d (p < 0.05). The emergence of dyskinesia had no association with the initiation time of levodopa, and if the latter was more than 4 years, the duration of time on chronic levodopa free of motor complications was significantly shortened.Conclusions: We found risk factors for the prediction of dyskinesia. Our data shows that physicians should be cautious if the LEDD exceeds 300 mg/d. The development of dyskinesia was not correlated with the time of levodopa initiation