AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202501000-00033/figure1/v/2024-05-14T021156Z/r/image-tiff The E3 ubiquitin ligase, carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP), also functions as a co-chaperone and plays a crucial role in the protein quality control system. In this study, we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer's disease. We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain. CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests, reduced amyloid-ß plaques, and decreased the expression of both amyloid-ß and phosphorylated tau. CHIP also alleviated the concentration of microglia and astrocytes around plaques. In APP/PS1 mice of a younger age, CHIP overexpression promoted an increase in ADAM10 expression and inhibited ß-site APP cleaving enzyme 1, insulin degrading enzyme, and neprilysin expression. Levels of HSP70 and HSP40, which have functional relevance to CHIP, were also increased. Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated, which may also reflect a potential mechanism for the neuroprotective effect of CHIP. Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice. Indeed, overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer's disease.

Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease.

Background: Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD. Objective: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies. Methods: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy. Results: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity. Conclusion: P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.

Association between irritable bowel syndrome and Parkinson's disease by Cohort study and Mendelian randomization analysis.

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS.

Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis.

BACKGROUND: Commonly clinically diagnosed with relapsing polychondritis (RP), vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) is a recently identified autoinflammatory disease caused by UBA1 somatic mutations. The low frequency and dynamic changes challenge the accurate detection of somatic mutations. The present study monitored these mutations in Chinese patients with RP. We included 44 patients with RP. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood. Droplet digital polymerase chain reaction (ddPCR) was performed to screen low-prevalence somatic variants. RESULTS: Multiple ddPCR detections were performed using available blood samples collected at different follow-up time points. Three male patients were UBA1 somatic mutation carriers. Sanger sequencing detected the somatic UBA1 variant c.122T > C (p.Met41Thr) in two male patients. Initial ddPCR confirmed the variant in the two patients, with allele fractions of 73.75% and 88.46%, respectively, while yielding negative results in other patients. Subsequent ddPCR detected the somatic variant (c.122T > C) with low prevalence (1.02%) in another male patient from blood samples collected at a different time point, and confirmed dynamically fractional abundance in one patient with VEXAS, with allele fractions of 73.75%, 61.28%, 65.01%, and 73.75%. Nine patients assessed by ddPCR at different time points remained negative. CONCLUSION: We report UBA1 variants in patients with RP in the Chinese population for the first time. Multiple ddPCR detections from samples collected at different time points can enhance sensitivity and should be considered for patients with initial negative ddPCR results.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Myasthenia Gravis and Ischemic Stroke: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Autoimmune diseases are associated with cardiovascular and cerebrovascular diseases. However, whether myasthenia gravis (MG) and ischemic stroke (IS) are causally related remains unclear. OBJECTIVES: This study aimed to evaluate potential causal links between MG and IS using bidirectional Mendelian randomization (MR). METHODS: We conducted a two-sample MR analysis to assess the potential associations between MG and IS. Genetic variants associated with MG and IS as well as their subtypes were extracted from genome-wide association studies by meta-analysis. The inverse-variance weighted method was used for the main MR analysis. Sensitivity analyses, including the MREgger, simple mode, simple median, weighted mode, and weighted median approaches were applied to test the robustness of the results. RESULTS: The MR analyses indicated no causal effects of general MG on IS of all causes (odds ratio [OR] = 0.990, 95% confidence interval [CI]: 0.953-1.029, p = 0.615), large vessel atherosclerosis stroke (OR = 0.943, 95% CI: 0.856-1.039, p = 0.233), cardioembolic stroke (OR = 0.975, 95% CI: 0.867-1.096, p = 0.670), and small vessel occlusion stroke (OR = 1.059, 95% CI 0.974-1.150, p = 0.178). Subgroup analyses indicated no causal effects of early- or late-onset MG on IS and its subtypes (all p > 0.05). The reverse MR analysis showed no significant causal associations of IS on MG (all p > 0.05). CONCLUSION: Bidirectional MR analysis did not provide evidence to support a causal relationship between genetically predicted MG and IS, although observational studies have found such a potential link.

Meningeal immunity and neurological diseases: new approaches, new insights.

The meninges, membranes surrounding the central nervous system (CNS) boundary, harbor a diverse array of immunocompetent immune cells, and therefore, serve as an immunologically active site. Meningeal immunity has emerged as a key factor in modulating proper brain function and social behavior, performing constant immune surveillance of the CNS, and participating in several neurological diseases. However, it remains to be determined how meningeal immunity contributes to CNS physiology and pathophysiology. With the advances in single-cell omics, new approaches, such as single-cell technologies, unveiled the details of cellular and molecular mechanisms underlying meningeal immunity in CNS homeostasis and dysfunction. These new findings contradict some previous dogmas and shed new light on new possible therapeutic targets. In this review, we focus on the complicated multi-components, powerful meningeal immunosurveillance capability, and its crucial involvement in physiological and neuropathological conditions, as recently revealed by single-cell technologies.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson's disease.

The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2-related PD completely reproduce the features of PD, and no transgenic or knock-in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α-synuclein and p-α-synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin-degrading enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2-related PD.

Spinocerebellar Ataxia Type 10 with Atypical Clinical Manifestation in Han Chinese.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant cerebellar ataxia accompanied by extracerebellar signs and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of ATXN10. Cases of SCA10, formerly confined to America, have been reported in Europe and Asia. In the present study, we aim to report an atypical SCA10 family in China and provide a reference for the diagnosis of SCA10 in Asia by comparing their clinical and genetic features with former SCA10 pedigrees. Genomic DNA was extracted from patients and subjected to RP-PCR (repeat-primed PCR), Southern blotting, and haplotype analysis to determine the genetic pathogenesis. Patients with SCA10 in this pedigree demonstrated atypical SCA10 manifestations, including the absence of seizures and ocular abnormalities. Magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients with available data. RP-PCR and Southern blotting revealed abnormal expansion. Analysis of single nucleotide polymorphisms (SNPs) surrounding the SCA10 locus in the proband and other affected family members revealed the "C-expansion-G-G-C" haplotype, consistent with former studies. These findings imply that the SCA10 mutation may have occurred before the Amerindian migration from East Asia to North America. It also suggested that SCA10 should be taken into account during differential diagnosis in patients of Asian ancestry, even if they do not present with typical features such as epilepsy.

Peripheral immune markers and amyotrophic lateral sclerosis: a Mendelian randomization study.

Introduction: The peripheral immune system changes in amyotrophic lateral sclerosis (ALS), but the causal relationship between the two is still controversial. Methods: In this study, we aimed to estimate the causal relationship between peripheral immune markers and ALS using a two-sample Mendelian randomization method. Genome-wide association study (GWAS) data on peripheral blood immune traits from European populations were used for exposure, and ALS summary statistics were used as the outcome. The causal relationship was evaluated by inverse variance weighting, MR-Egger, and weighted median methods and verified by multiple sensitivity analysis. Results: We found that the increase of one standard deviation of lymphocyte count is related to reducing ALS risk. CD3 on effector memory CD4+ T cell, HLA DR+ CD4+ T cell, effector memory CD8+ T cell, terminally differentiated CD8+ T cell and CD28- CD8+ T cell is also a protective factor for ALS. Among the circulating immune protein, the increase of one standard deviation of α-2-macroglobulin receptor-associated protein (α-2-MRAP) and C4b showed associated with low risk of ALS, while Interleukin-21 (IL-21) increases the risk of ALS. Discussion: Our study further reveals the important role of peripheral immune activity in ALS.

Increased PRR14 and VCAM-1 level in serum of patients with Parkinson's disease.

Background: Regarding the complexity of Parkinson's disease (PD), the identification of reliable biomarkers is of great significance for improving the accuracy of diagnosis and monitoring disease progression. Recently, some studies suggested that serum proline-rich protein 14 (PRR14), vascular cell adhesion molecule-1 (VCAM-1), and soluble CD163 (sCD163) factors may be associated with PD, even as potential biomarkers. However, the role of these serum factors is still unclear. Objectives: This study aimed to explore the alterations of serum PRR14, VCAM-1, and sCD163 levels during PD progression, and their association with disease-related variables of PD. Methods: We performed the assessment of scale tests and the detection of serum samples in patients with PD (n = 100) and healthy controls (HCs, n = 100). Furthermore, we investigated the association between serum factors and sex, cognitive impairments, H&Y (Hohn and Yahr), age at onset (AAO), and other variables in patients with PD. Results: Patients with PD exhibited increased PRR14 and VCAM-1 serum levels compared with HCs. No significant differences were found in serum levels of sCD163. Subgroup analysis uncovered increased VCAM-1 in the female and male subgroups (PD and HCs). Among patients with PD, decreased PRR14 and increased VCAM-1 were associated with severer cognitive impairments and severer PD (H&Y), respectively. Bivariate correlation analysis revealed that there was a positive correlation between VCAM-1 and AAO. Conclusions: Increased serum levels of PRR14 and VCAM-1 suggest that inflammation and defective autophagy may play vital roles in the pathogenesis of PD. However, the potential mechanisms remain to be elucidated.

Advances in Potential Cerebrospinal Fluid Biomarkers for Autoimmune Encephalitis: A Review.

Autoimmune encephalitis (AE) is a severe inflammatory disease of the brain. Patients with AE demonstrate amnesia, seizures, and psychosis. Recent studies have identified numerous associated autoantibodies (e.g., against NMDA receptors (NMDARs), LGI1, etc.) involved in the pathogenesis of AE, and the levels of diagnosis and treatment are thus improved dramatically. However, there are drawbacks of clinical diagnosis and treatment based solely on antibody levels, and thus the application of additional biomarkers is urgently needed. Considering the important role of immune mechanisms in AE development, we summarize the relevant research progress in identifying cerebrospinal fluid (CSF) biomarkers with a focus on cytokines/chemokines, demyelination, and nerve damage.

Dysregulation of peripheral monocytes and pro-inflammation of alpha-synuclein in Parkinson's disease.

BACKGROUND AND OBJECTIVES: Mounting evidence indicates the involvement of the innate immune system in Parkinson's disease (PD). Nevertheless, the implications of peripheral monocytes have not been fully elucidated. Although alpha-synuclein (α-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of α-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar α-synuclein. METHODS: Using flow cytometry, we explored the distribution of monocytic subpopulations. We also investigated the actions of peripheral monocytes in response to lipopolysaccharides (LPS) and to fibrillar α-synuclein stimuli by measuring inflammatory molecule levels in post-culture supernatants. RESULTS: Classical monocytes were enriched, in parallel with lower proportions of intermediate and nonclassical monocytes in patients with PD than in controls. Lower levels of TNF-α and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar α-synuclein stimuli induced high levels of TNF-α, IL-1ß, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-α and IL-6 was lower in patients with PD than that in normal controls under the same stimulation. CONCLUSION: Our results revealed a strong dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli, and the proinflammatory effect of α-synuclein on monocytes. Further studies are needed to clarify the specific mechanisms by which these immunological abnormalities are present in PD to open the possibility of immunoregulatory therapy.

Generation of an induced pluripotent stem cell line (ZZUi036-A) derived from skin fibroblasts of a Neuronal intranuclear inclusion disease patient with GGC repeat expansion in the NOTCH2NLC gene.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by cognitive impairment, extrapyramidal symptoms, white matter lesions and muscle weakness. The cause of NIID is a repeat amplification of a GGC mutation in the 5 ' untranslated region (UTR) of the NOTCH2NLC gene. Using the non-integrating Sendai virus to deliver the Klf4, OCT3/4, SOX2 and C-MYC factors, fibroblasts obtained from a NIID patient were reprogrammed to generate an induced pluripotent stem cell (iPSC) line (ZZUi036-A). Our approach provided a resource for the investigation of the mechanism of the disease, drug research, cell transplantation and gene therapy.

Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population.

Cerebral small vessel disease (CSVD) is a syndrome of clinical, neuroimaging, and neuropathological manifestations caused by disorders that affect small cerebral vessels. Although the pathogenesis of the disease remains unclear, some studies have demonstrated that genetic variants contribute to the development of CSVD. Our study aimed to explore the genetic characteristics of CSVD in the Chinese Han population. We enrolled 182 sporadic CSVD Chinese Han patients whose magnetic resonance imaging results showed grade 2-3 white matter lesions. Target region sequencing of seven monogenic CSVD-related genes, including NOTCH3, HTRA1, COL4A1, COL4A2, GLA, TREX1, and CTSA, was performed, and we identified pathogenic variants by screening the sequencing results and functional predictive analysis. All variants were predicted to be pathogenic by the SIFT Score, Polymorphism Phenotyping-2 score, Mutation Taster, Splice site score calculation, and MaxEntScan. All variants were validated in 300 healthy controls. In total, eight variants were identified in patients with CSVD, including five novel variants, c.1774C>T (NOTCH3), c.3784C>T (NOTCH3), c. 1207C>T (HTRA1), and c. 1274+1G> A (HTRA1), c.1937G>C (COL4A1) and three reported mutations. None of these variants were present in 300 healthy controls. No pathogenic variants in COL4A2, GLA, TREX1, and CTSA were detected. This study identified five novel variants in CSVD-related genes in Chinese Han patients with sporadic CSVD. Our results expand the genetic profile of CSVD.

GIPC1 CGG Repeat Expansion Is Associated with Movement Disorders.

OBJECTIVE: CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders. METHODS: We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls. RESULTS: No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored >40 CGG repeats in GIPC1, with 11 of these patients harboring >60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (<0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions. INTERPRETATION: The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022;91:704-715.

Neuroinflammation in Parkinson's Disease: Triggers, Mechanisms, and Immunotherapies.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disease involving multiple etiologies and pathogenesis, in which neuroinflammation is a common factor. Both preclinical experiments and clinical studies provide evidence for the involvement of neuroinflammation in the pathophysiology of PD, although there are a number of key issues related to neuroinflammatory processes in PD that remain to be addressed. In this review, we highlight the relationship between the common pathological mechanisms of PD and neuroinflammation, including aggregation of α-synuclein, genetic factors, mitochondrial dysfunction, and gut microbiome dysbiosis. We also describe the two positive feedback loops initiated in PD after the immune system is activated, and their role in the pathogenesis of PD. In addition, the interconnections and differences between the central and peripheral immune systems are discussed. Finally, we review the latest progress in immunotherapy research for PD patients, and propose future directions for clinical research.