TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Integrated full-length transcriptome and metabolome analysis reveals the defence response of melon to gummy stem blight.

Gummy stem blight (GSB), a widespread disease causing great loss to cucurbit production, has become a major threat to melon cultivation. However, the melon-GSB interaction remains largely unknown. Here, full-length transcriptome and widely targeted metabolome were used to investigate the defence responses of resistant (PI511089) and susceptible (Payzawat) melon accessions to GSB pathogen infection at 24 h. The biosynthesis of secondary metabolites and MAPK signalling pathway were specifically enriched for differentially expressed genes in PI511890, while carbohydrate metabolism and amino acid metabolism were specifically enriched in Payzawat. More than 1000 novel genes were identified and MAPK signalling pathway was specifically enriched for them in PI511890. There were 11 793 alternative splicing events involving in the defence response to GSB. Totally, 910 metabolites were identified in Payzawat and PI511890, and flavonoids were the dominant metabolites. Integrated full-length transcriptome and metabolome analysis showed eriodictyol and oxalic acid were the potential marker metabolites for GSB resistance in melon. Moreover, posttranscription regulation was widely involved in the defence response of melon to GSB pathogen infection. These results not only improve our understanding on the interaction between melon and GSB, but also facilitate the genetic improvement of melon with GSB resistance.

Motor progression marker for newly diagnosed drug-naïve patients with Parkinson's disease: A resting-state functional MRI study.

The effective early prediction of clinical outcomes of Parkinson's disease (PD) is of great significance in the implementation of appropriate interventions. We aimed to propose a method based on the use of baseline resting-state functional characteristics (i.e., fractional amplitude of low-frequency fluctuations, fALFF) to predict motor progression in PD patients. Resting-state functional magnetic resonance imaging was performed on 48 newly-diagnosed drug-naïve PD patients and 27 age- and sex- matched healthy controls (HCs). Two PD subgroups were defined with different annual increase of Unified PD Rating Scale Part III motor scores. Least absolute shrinkage and selection operator regression analysis was performed to explore the baseline region-functional indicators for PD discrimination as well as the predictors for future motor deficits. Two significant models composed of baseline fALFF values from cerebral subregions were proposed. The classification model that distinguished PD patients from HCs (area under the curve [AUC] = 0.897) showed the most significant imaging characteristics in the putamen and precentral gyrus. The other prediction model that evaluated the degree of future deterioration of motor symptoms in PD patients (AUC = 0.916) showed the most significant imaging characteristics in the superior occipital gyrus and caudate nucleus. Furthermore, the increased regional function in bilateral caudate nuclei was correlated with the lower annual increase in motor deficits in all PD patients. The caudate nucleus might be the core region responsible for future motor deficits in newly-diagnosed PD patients, which may aid the development of disease progression preventive strategies in clinical practice.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects. METHODS: A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR. RESULTS: Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 (EPHX2), SERPINB1 and SIGLEC11) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2, SERPINB1 or SIGLEC11. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

Fluorine-Containing Passivation Layer via Surface Chelation for Inorganic Perovskite Solar Cells.

Minimizing surface defect is vital to further improve power conversion efficiency (PCE) and stability of inorganic perovskite solar cells (PSCs). Herein, we designed a passivator trifluoroacetamidine (TFA) to suppress CsPbI3-x Brx film defects. The amidine group of TFA can strongly chelate onto the perovskite surface to suppress the iodide vacancy, strengthened by additional hydrogen bonds. Moreover, three fluorine atoms allow strong intermolecular connection via intermolecular hydrogen bonds, thus constructing a robust shield against moisture. The TFA-treated PSCs exhibit remarkably suppressed recombination, yielding the record PCEs of 21.35 % and 17.21 % for 0.09 cm2 and 1.0 cm2 device areas, both of which are the highest for all-inorganic PSCs so far. The device also achieves a PCE of 39.78 % under indoor illumination, the highest for all-inorganic indoor photovoltaic devices. Furthermore, TFA greatly improves device ambient stability by preserving 93 % of the initial PCE after 960 h.

Identifying novel proteins underlying schizophrenia via integrating pQTLs of the plasma, CSF, and brain with GWAS summary data.

BACKGROUND: Schizophrenia (SCZ) is a chronic and severe mental illness with no cure so far. Mendelian randomization (MR) is a genetic method widely used to explore etiologies of complex traits. In the current study, we aimed to identify novel proteins underlying SCZ with a systematic analytical approach. METHODS: We integrated protein quantitative trait loci (pQTLs) of the brain, cerebrospinal fluid (CSF), and plasma with the latest and largest SCZ genome-wide association study (GWAS) via a systematic analytical framework, including two-sample MR analysis, Steiger filtering analysis, and Bayesian colocalization analysis. RESULTS: The genetically determined protein level of C4A/C4B (OR = 0.70, p = 1.66E-07) in the brain and ACP5 (OR = 0.42, p = 3.73E-05), CNTN2 (OR = 0.62, p = 2.57E-04), and PLA2G7 (OR = 0.71, p = 1.48E-04) in the CSF was associated with a lower risk of SCZ, while the genetically determined protein level of TIE1 (OR = 3.46, p = 4.76E-05), BCL6 (OR = 3.63, p = 1.59E-07), and MICB (OR = 4.49, p = 2.31E-11) in the CSF were associated with an increased risk for SCZ. Pathway enrichment analysis indicated that genetically determined proteins suggestively associated with SCZ were enriched in the biological process of the immune response. CONCLUSION: In conclusion, we identified one protein in the brain and six proteins in the CSF that showed supporting evidence of being potentially associated with SCZ, which could provide insights into future mechanistic studies to find new treatments for the disease. Our results also supported the important role of neuroinflammation in the pathogenesis of SCZ.

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis.

BACKGROUND: The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS. METHODS: The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646. RESULTS: A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS. CONCLUSIONS: Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development.

Synchronous Surface Reconstruction and Defect Passivation for High-Performance Inorganic Perovskite Solar Cells.

The nonradiative charge recombination caused by surface defects and inferior crystalline quality are major roadblocks to further enhancing the performance of CsPbI3- x Brx perovskite solar cells (PSCs). Theoretical calculations indicate that sodium diethyldithiocarbamate (NaDDTC), a popular bacteriostatic benign material, can initiate multiple interactions with the CsPbI3- x Brx perovskite surface to effectively passivate the defects. The experimental results reveal that the NaDDTC can indeed passivate the electron trap states and lock active sites for charge traps and water adsorption. In addition, it is found that a solid-state reaction is triggered for perovskite crystal regrowth by the NaDDTC post-treatment, which not only enlarges grain size for reducing the density of grain boundary defects but also compensates some surface defects induced by the primary film growth. Consequently, the power conversion efficiency (PCE) of the CsPbI3- x Brx PSC is increased to as high as 20.40%, with significant improvement in fill factor and open-circuit voltage (VOC ), making it one of the highest for this type of solar cell. Furthermore, the optimized devices exhibit better environmental stability. Overall, this robust synchronous strategy provides efficient surface reconstruction and defect passivation for achieving both high PCE and stable inorganic perovskite.

Neurofilament Light Chain Predicts Disease Severity and Progression in Multiple System Atrophy.

BACKGROUND: Neurofilament light chain (NFL), a potential biomarker of multiple system atrophy (MSA), has been reported in several studies. OBJECTIVES: The objective of this study was to investigate whether plasma NFL levels are correlated with the progression of motor and cognition function in MSA. METHODS: Patients with MSA were part of a prospective cohort study with assessments at baseline and after 1 year. Plasma NFL was quantified using ultrasensitive Simoa technology. RESULTS: A total of 91 patients with MSA and 60 healthy controls (HCs) were enrolled. NFL levels increased from baseline to 1-year follow-up (P = 0.010). Baseline plasma NFL levels were significantly associated with motor severity and progression in patients with MSA (P < 0.05) but not with cognitive progression (P > 0.05). CONCLUSIONS: Plasma NFL is a reliable biomarker for the disease severity of MSA and monitoring the progression of MSA, but not the progression of cognition. © 2021 International Parkinson and Movement Disorder Society.

Genetic Determinants of Survival in Parkinson's Disease in the Asian Population.

BACKGROUND: Patients with Parkinson's disease (PD) have reduced life expectancy compared to the general population. Genetic variation was shown to play a role in the heterogeneity of survival for patients with PD, although the underlying genetic background remains poorly studied. OBJECTIVE: The aim was to explore the genetic determinants influencing the survival of PD. METHODS: We performed a genome-wide association analysis using a Cox proportional hazards model in a longitudinal cohort of 1080 Chinese patients with PD. Furthermore, we built a clinical-genetic model to predict the survival of patients using clinical variables combined with polygenic risk score (PRS) of survival of PD. RESULTS: The cohort was followed up for an average of 7.13 years, with 85 incidents of death. One locus rs12628329 (RPL3) was significantly associated with reduced survival time by ~10.8 months (P = 2.72E-08, ß = 1.79, standard error = 0.32). Functional exploration suggested this variant could upregulate the expression of RPL3 and induce apoptosis and cell death. In addition, adding PRS of survival in the prediction model substantially improved survival predictability (concordance index [Cindex]: 0.936) compared with the clinical model (Cindex: 0.860). CONCLUSIONS: These findings improve the current understanding of the genetic cause of survival of PD and provide a novel target RPL3 for further research on PD pathogenesis and potential therapeutic options. Our results also demonstrate the potential utility of PRS of survival in identifying patients with shorter survival and providing personalized clinical monitoring and treatment. © 2022 International Parkinson and Movement Disorder Society.

Mutation Screening of TFG in α-Synucleinopathy and Amyotrophic Lateral Sclerosis.

BACKGROUND: Recently, p.R383H in TFG was identified as the disease cause in a family with α-synucleinopathy and amyotrophic lateral sclerosis (ALS). However, no further replication has been conducted in larger cohorts. OBJECTIVE: The aim was to explore the genetic role of TFG in α-synucleinopathy and ALS. METHODS: We analyzed the rare protein-coding variants in patients with Parkinson's disease (PD), ALS, multiple system atrophy (MSA), spastic paraplegia (N = 2709), and 7536 controls with whole-exome sequencing. RESULTS: Nine rare variants were identified in PD and two in MSA. One PD patient carried the same variant p.R383H. Similarly, this patient developed early-onset PD with bradykinesia and rigidity on the left side as the initial symptoms. However, at the gene level, rare variants of TFG were not enriched in patients. CONCLUSIONS: Rare variants of TFG were not enriched in α-synucleinopathy and ALS. However, we could not deny the potential pathogenicity of specific variants such as p.R383H. Further exploration is still necessary. © 2022 International Parkinson and Movement Disorder Society.

Spatial-temporal pattern of propagation in amyotrophic lateral sclerosis and effect on survival: A cohort study.

BACKGROUND AND PURPOSE: Clarification of propagation patterns in amyotrophic lateral sclerosis (ALS) is challenging, but understanding these has implications for individual prognostication and clinical trial design. However, systematic knowledge in this area is lacking. The aim of this study was to characterize the spatial and temporal features of propagation patterns in ALS, and to evaluate the association between propagation patterns and survival. METHODS: A cohort of 833 patients with ALS, diagnosed between January 2018 and December 2019 and followed to August 2021, was analysed. Spatial and temporal features of propagation patterns were determined based on the involved functional regions (bulbar, cervical, thoracic/respiratory and lumbar) in time order. The final propagation pattern was identified in patients with at least three functional regions involved. Kaplan-Meier analysis and Cox regression analysis were performed. RESULTS: During a median follow-up of 21.2 months, 19 final propagation patterns were identified in 657 patients (78.9%). In survival analysis, we found that the earlier the respiratory functional region becomes involved, the higher the risk of death (time order: 1st: hazard ratio [HR], 3.35, 95% confidence interval [CI] 1.23-9.15; 2nd: HR 2.45, 95% CI 1.55-3.87; 3rd: HR 1.94, 95% CI 1.52-2.49), adjusting for age, sex, diagnostic delay, revised ALS Functional Rating Scale score, cognitive impairment and riluzole. Shorter interval time between involved regions was an independent adverse prognostic factor. CONCLUSIONS: The propagation patterns of ALS are varied. The order in which the respiratory region becomes involved and the interval time between involvement of functional regions are predictors for prognosis.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

Genetic Modifiers of Age at Onset for Parkinson's Disease in Asians: A Genome-Wide Association Study.

BACKGROUND: Age at onset (AAO) is an essential feature of Parkinson's disease (PD) and can help predict disease progression and mortality. Identification of genetic variants influencing AAO of PD could lead to a better understanding of the disease's biological mechanism and provide clinical guidance. However, genetic determinants for AAO of PD remain mostly unknown, especially in the Asian population. OBJECTIVES: To identify genetic determinants for AAO of PD in the Asian population. METHODS: We performed a genome-wide association meta-analysis on AAO of PD in 5166 Chinese patients with PD (Ndiscovery  = 3628, Nreplication  = 1538). We then conducted a further cross-ethnic meta-analysis using our results and summary statistics for the AAO of PD from the European population. RESULTS: The total heritability of AAO of PD was around 0.10 ~ 0.14, similar to that (~0.11) estimated in populations of European ancestry. One novel significant intergenic locus rs9783733 (NDN; PWRN4) was identified (P = 3.14E-09, beta = 2.30, SE = 0.39). Remarkably, this variant could delay AAO of PD by ~2.43 years, with a more considerable effect on males (~3.18 years) than females (~1.45 years). The variant was suggestively significant in the cross-ethnic meta-analysis and suggested a positive selection in the East Asian population. Additionally, cross-ethnic meta-analysis identified a significant locus rs356203 in SNCA (P = 2.35E-11, beta = -0.71, SE = 0.01). CONCLUSIONS: These findings improve the current understanding of the genetic etiology of AAO of PD in different ethnic groups, and provide a new target for further research on PD pathogenesis and potential therapeutic options. © 2021 International Parkinson and Movement Disorder Society.

Abnormal eye movements in spinocerebellar ataxia type 3.

BACKGROUND: Abnormal eye movements are common in spinocerebellar ataxias Type 3 (SCA3). We conducted the research to explore the frequency of abnormal eye movements in Chinese patients with SCA3, to compare the demographic and clinical characteristics between SCA3 patients with and without each type of abnormal eye movement, and to explore the correlation between abnormal eye movements and the severity of ataxia. METHODS: Seventy-four patients with SCA3 were enrolled in this cross-sectional study. Six types of abnormal eye movements including impaired smooth pursuit, increased square-wave jerks (SWJ), gaze-evoked nystagmus (GEN), slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy were evaluated by experienced neurologists. The severity of ataxia was evaluated by Scale for the Assessment and Rating of Ataxia (SARA). RESULTS: The prevalence of impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy in Chinese SCA3 patients was 28.4, 13.5, 78.4, 41.9, 23.0, and 5.4%, respectively. SCA3 patients with GEN had higher scores of International Cooperative Ataxia Rating Scale (ICARS-IV) and total ICARS, and longer length of CAG repeat than patients without GEN. SCA3 patients with slowing of saccades had a longer disease duration, higher scores of ICARS-I, ICARS-II, total ICARS and SARA than patients without slowing of saccades. SCA3 patients with saccadic hypo/hypermetria had higher scores of ICARS-III, ICARS-IV, and SARA than patients without saccadic hypo/hypermetria. The demographic and clinical characteristics did not differ significantly between SCA3 patients with and without impaired smooth pursuit, increased SWJ, or supranuclear gaze palsy. Multivariate linear regression showed that the number of abnormal eye movements (0-6), disease duration, Hamilton Depression Rating Scale-24 (HDRS-24) score, and CAG repeat length were positively correlated with SARA score, whereas Montreal Cognitive Assessment (MoCA) score was negatively correlated with SARA score in SCA3. CONCLUSIONS: An increased number of abnormal eye movement types correlated with the severity of ataxia in SCA3.

Rational Surface-Defect Control via Designed Passivation for High-Efficiency Inorganic Perovskite Solar Cells.

Iodine vacancies (VI ) and undercoordinated Pb2+ on the surface of all-inorganic perovskite films are mainly responsible for nonradiative charge recombination. An environmentally benign material, histamine (HA), is used to passivate the VI in perovskite films. A theoretical study shows that HA bonds to the VI on the surface of the perovskite film via a Lewis base-acid interaction; an additional hydrogen bond (H-bond) strengthens such interaction owing to the favorable molecular configuration of HA. Undercoordinated Pb2+ and Pb clusters are passivated, leading to significantly reduced surface trap density and prolonged charge lifetime within the perovskite films. HA passivation also induces an upward shift of the energy band edge of the perovskite layer, facilitating interfacial hole transfer. The combination of the above raises the solar cell efficiency from 19.5 to 20.8 % under 100 mW cm-2 illumination, the highest efficiency so far for inorganic metal halide perovskite solar cells (PSCs).

MicroRNA-183-5p is stress-inducible and protects neurons against cell death in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. A fundamental pathogenesis of ALS is the prolonged cell stress in neurons, which is caused by either accumulation of protein aggregates or reactive oxygen species. However, the mechanistic link between stress sensing and cell death is unsettled. Here, we identify that miR-183-5p, a neuron-enriched miRNA, couples stress sensing and cell death programming in ALS. miR-183-5p is immediately induced by hydrogen peroxide, tunicamycin or TNF-α in neurons. The overexpression of miR-183-5p increases neuron survival under stress conditions, whereas its knockdown causes neuron death. miR-183-5p coordinates apoptosis and necroptosis pathways by directly targeting PDCD4 and RIPK3, and thus protects neurons against cell death under stress conditions. The consistent reduction of miR-183-5p in ALS patients and mouse models enhances the notion that miR-183-5p is a central regulator of motor neuron survival under stress conditions. Our study supplements current understanding of the mechanistic link between cell stress and death/survival, and provides novel targets for clinical interventions of ALS.

Mutation Analysis of DNAJC Family for Early-Onset Parkinson's Disease in a Chinese Cohort.

BACKGROUND: Recently, members of the DnaJ homolog C (DNAJC) family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies are based on European-ancestry population and no comprehensive analysis is further conducted. OBJECTIVES: In this study, we aim to systematically explore the associations of DNAJCs by genetic analysis in a large Chinese early-onset PD (EOPD) cohort. METHODS: Rare variants were identified using whole exome sequencing in a cohort of 664 unrelated patients with EOPD. Allelic association analysis was performed with Fisher's exact test to clarify the associations at allele level. Gene-based burden analysis was conducted for both rare variants and damaging variants to illuminate the involvement of DNAJCs in EOPD at the gene level. RESULTS: In total, 61 rare variants were identified in the current study. At the allele level, 2 variants, p.T1109R and p.L174H, in DNAJC26 were significant after Bonferroni correction; 2 variants, p.V1271A and p.A476V, in DNAJC26; 2 variants, p.M477T and p.D1670G, in DNAJC13; 1 variant, p.L19I, in DNAJC10; and 1 variant, p.N526S, in DNAJC6 reached nominal significance. Moreover, a novel compound heterozygous mutation in DNAJC6 was identified. At the gene level, gene-based burden analysis showed a clear enrichment of rare variants in DNAJC26 in patients with EOPD, but not other DNAJCs. CONCLUSIONS: Our work identifies novel rare variants of DNAJC26 to be associated with EOPD and enhances our understanding of the role of DNAJC family members in EOPD. © 2020 International Parkinson and Movement Disorder Society.

Evaluating the Role of SNCA, LRRK2, and GBA in Chinese Patients With Early-Onset Parkinson's Disease.

BACKGROUND: Defects in the α-synuclein, leucine-rich repeat kinase 2, or glucocerebrosidase genes have been regarded as essential contributors to PD. However, genetic variability of these genes with respect to early-onset PD remains poorly defined for the Chinese demographic. OBJECTIVES: We aim to systematically characterize the clinical and genetic architecture of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in Chinese early-onset PD patients. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in 662 Chinese early-onset PD patients. Haplotype and burden analyses were conducted to investigate the role of rare variants of these three genes in early-onset PD. RESULTS: Sixty rare variants, including 23 novel variants, were identified in 73 patients (11.0%). Frequencies of patients with rare pathogenic/likely pathogenic variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase were 0.6%, 3.0%, and 5.4%, respectively. Evidences of two founder events exclusive to Asians were identified in 2 patients with leucine-rich repeat kinase 2 p.R1441C and 3 patients with α-synuclein p.A53V. Gene-based burden analysis supported glucocerebrosidase as a strong risk factor for early-onset PD, but argued against over-representation of rare variants in α-synuclein or leucine-rich repeat kinase 2 in early-onset PD. Clinically, no differences in motor or nonmotor symptoms were found between glucocerebrosidase variants carriers, and noncarriers or between leucine-rich repeat kinase 2 carriers and noncarriers. Patients with α-synuclein variants showed both rapid progression and worse cognitive impairment. CONCLUSION: Our study provides a better understanding of the clinical and genetic correlations of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in early-onset PD, which may be beneficial for drafting genetic scanning strategies and evaluating disease progression. © 2020 International Parkinson and Movement Disorder Society.