Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) ...is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
Objective:
To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21‐q23.
Methods:
We previously characterized a large ...Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.
Results:
We identified heterozygous mutations in the voltage‐gated potassium channel Kv4.3‐encoding gene KCND3: an in‐frame 3‐nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A‐type K+ channel conductance in whole cell patch‐clamp recordings.
Interpretation:
Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859–869.
Ataxia is one of the most devastating symptoms of many neurodegenerative disorders. As of today, there is not any effective treatment to retard its progression. Mesenchymal stem cells (MSCs) have ...shown promise in treating neurodegenerative diseases. We hereby report the results of a phase I/IIa clinical study conducted in Taiwan to primarily evaluate the safety, tolerability, and, secondarily, the possible efficacy of intravenous administration of allogeneic adipose tissue-derived MSCs from healthy donors. Six patients with spinocerebellar ataxia type 3 and one with multiple system atrophy-cerebellar type were included in this open-label study with intravenous administration of 10
6
cells/kg body weight. The subjects were closely monitored for 1 year for safety (vital signs, complete blood counts, serum biochemical profiles, and urinalysis) and possible efficacy (scale for assessment and rating of ataxia and sensory organization testing scores, metabolite ratios on the brain magnetic resonance spectroscopy, and brain glucose metabolism of 18-fluorodeoxyglucose using positron emission tomography). No adverse events related to the injection of MSCs during the 1-year follow-up were observed. The intravenous administration of allogeneic MSCs seemed well tolerated. Upon study completion, all patients wished to continue treatment with the allogeneic MSCs. We conclude that allogeneic MSCs given by intravenous injection seems to be safe and tolerable in patients with spinocerebellar ataxia type 3, thus supporting advancement of the clinical development of allogeneic MSCs for the treatment of spinocerebellar ataxias (SCAs) in a randomized, double-blind, placebo-controlled phase II trials.
Background and purpose
Multiple system atrophy (MSA) has no definitive genetic or environmental (G‐E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This ...study was undertaken to investigate the integrated effect of G‐E factors associated with MSA and its subtypes, MSA‐P and MSA‐C.
Methods
A consecutive case–control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model.
Results
A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G‐E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval CI = 0.671–0.847). Modulated risk of MSA‐C, with MSA‐P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683–0.815).
Conclusions
Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G‐E interactions and MSA etiopathogenesis warrant further investigation.
This consecutive case–control study enrolled 207 multiple system atrophy (MSA) patients and 136 healthy controls from two hospitals, and found that MSA risk significantly correlated with COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers. The risk of MSA‐C compared to MSA‐P was significantly correlated with COQ2_rs148156462 (TT) × alcohol nonusers, SNCA_rs11931074 (GG) × well water former drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure.
Abstract
Differentiation cerebellar multiple systemic atrophy (MSA-C) from spinocerebellar ataxia (SCA) is important. The “hot cross bun” sign (HCBS) at pons and magnetic resonance spectroscopy (MRS) ...are helpful. However, the prevalence of HCBS and the alteration of cerebellar MRS parameters are evolving with disease progression. We hypothesized that since the HCBS and MRS are evolving with time, different parameters for differentiation of MSA-C and SCA are required at different disease stages. The aim of this study was to evaluate the HCBS and MRS changes in patients with MSA-C and SCA at different disease stages. A total of 398 patients with molecularly confirmed SCA (SCA1, 2, 3, 6, 17) and 286 patients diagnosed with probable MSA-C (without mutations in SCA1, 2, 3, 6, 17 genes), who had received brain magnetic resonance imaging (MRI) and MRS from January 2000 to January 2020, were recruited. Twenty-five patients were molecularly identified as having SCA1, 68 as SCA2, 253 as SCA3, 34 as SCA6, and 18 as SCA17. We compared their clinical parameters and neuroimaging features at different disease stages. The presence of HCBS was assessed using an axial T2 fast spin-echo or FLAIR sequence. Proton MRS was recorded with voxel of interest focusing on cerebellar hemispheres and cerebellar vermis and avoiding cerebrospinal fluid spaces space using a single-voxel stimulated echo acquisition mode sequence. We found that patients with MSA-C tend to have a higher prevalence of pontine HCBS, worse Scale for the Assessment and Rating of Ataxia scores, lower cerebellar
N
-acetyl aspartate (NAA)/creatinine (Cr), and choline (Cho)/Cr, compared to patients with SCA at corresponding disease stages. In MSA-C patients with a disease duration < 1 year and without pontine HCBS, a cerebellar NAA/Cr ≤ 0.79 is a good indicator of the possibility of MSA-C. By using the pontine HCBS and cerebellar MRS, discerning MSA-C from SCA became possible. This study provides cutoff values of MRS to serve as clues in differentiating MSA-C from SCAs.
Spinocerebellar ataxias 2 and 3 (SCA2 and SCA3) are dominantly inherited neurodegenerative diseases caused by expansion of polyglutamine-encoding CAG repeats in the affected genes. The etiology of ...these disorders is known to involve widespread loss of neuronal cells in the cerebellum, however, the mechanisms that contribute to cell death are still elusive. Here we established SCA2 and SCA3 induced pluripotent stem cells (iPSCs) and demonstrated that SCA-associated pathological features can be recapitulated in SCA-iPSC-derived neurons. Importantly, our results also revealed that glutamate stimulation promotes the development of disease-related phenotypes in SCA-iPSC-derived neurons, including altered composition of glutamatergic receptors, destabilized intracellular calcium, and eventual cell death. Furthermore, anti-glutamate drugs and calcium stabilizer treatment protected the SCA-iPSC-derived neurons and reduced cell death. Collectively, our study demonstrates that the SCA-iPSC-derived neurons can recapitulate SCA-associated pathological features, providing a valuable tool to explore SCA pathogenic mechanisms and screen drugs to identify potential SCA therapeutics.
Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in ...distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3-6 and ...leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.
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