Bin Jiao

Identification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China

The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in white populations. To estimate the frequency of hexanucleotide repeats in patients with ALS and FTD from mainland China, we screened for C9orf72 in a cohort of 128 patients and 150 control subjects using the repeat-primed polymerase chain reaction method. We observed pathogenic repeat expansions in a family with ALS-FTD and in a patient with sporadic FTD. In the family with ALS-FTD, the proband and the 2 asymptomatic siblings exhibited C9orf72 repeat expansions, and the clinical feature of the proband was characterized by pure motor syndrome with no cognitive impairment. The patient with sporadic FTD presented primarily with deteriorating behavior and mental status. Genotype analysis revealed that the proband shared the previously reported 20-single nucleotide polymorphism risk haplotype, whereas the patient with sporadic FTD carried all single nucleotide polymorphisms except rs2814707-A. To our knowledge, this study is the first to report 2 C9orf72 mutation patients in mainland China, and they shared the similar risk haplotype identified in white populations, suggesting that ALS and FTD associated with C9orf72 mutation was probably derived from a single founder.

Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer's disease from mainland China.

Recently, 3 rare coding variants significantly associated with Alzheimers disease (AD) risk have been identified in western populations using whole exome sequencing method, including p.R47H in TREM2, p.V232M in PLD3, and p.T835M in UNC5C. To examine whether these variants are genetic risk factors in patients with AD from mainland China, we sequenced exon 2 of TREM2, exon 9 of PLD3, and exon 15 of UNC5C in Chinese Han population including 360 patients with AD and 400 control individuals. As a result, none of these 3 variants were identified in all subjects, however, 1 novel variant (p.A130V) in TREM2 and 4 novel variants (p.Q860H, p.T837K, p.S843G, and p.V836V) in UNC5C were detected in unrelated patients with late-onset AD. These findings suggest the 3 rare coding variants might not play an important role in AD risk in mainland China.

C9orf72 mutation is rare in Alzheimer's disease, Parkinson's disease, and essential tremor in China

GGGGCC repeat expansions in the C9orf72 gene have been identified as a major contributing factor in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the overlapping of clinical phenotypes and pathological characteristics between these two diseases and Alzheimers disease (AD), Parkinsons disease (PD), and essential tremor (ET), we speculated regarding whether C9orf72 repeat expansions also play a major role in these three diseases. Using the repeat-primed polymerase chain reaction method, we screened for C9orf72 in three groups of patients with PD (n = 911), AD (n = 279), and ET (n = 152) in the Chinese Han population. There were no pathogenic repeats (>30 repeats) detected in either the patients or controls (n = 314), which indicated that the pathogenic expansions of C9orf72 might be rare in these three diseases. However, the analysis of the association between the number of repeats (p = 0.001), short/intermediate genotype (short: <7 repeats; intermediate: ≥7 repeats) (odds ratio 1.37 [1.05, 1.79]), intermediate/intermediate genotype (Odds ratio 2.03 [1.17, 3.54]), and PD risks indicated that intermediate repeat alleles could act as contributors to PD. To the best of our knowledge, this study is the first to reveal the correlation between C9orf72 and Chinese PD, AD, or ET patients. Additionally, the results of this study suggest the novel idea that the intermediate repeat allele in C9orf72 is most likely a risk factor for PD.

Mutational analysis in early-onset familial Alzheimer's disease in Mainland China

Mutations of 3 causative genes, namely presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP), have been identified as the major causes of early-onset familial Alzheimers disease (EOFAD). Recently, a GGGGCC repeat expansion in the noncoding region of C9orf72 was also detected in some patients with clinically diagnosed familial Alzheimers disease. The prevalence of causative gene mutations in patients with EOFAD has been reported in previous studies but their prevalence remains unclear in Mainland China. The aim of this study was to characterize the common causative gene mutation spectrum and genotype-phenotype correlations in Chinese patients with EOFAD. Genetic screening for mutations in PSEN1, PSEN2, and APP was conducted in a total of 32 families with clinical diagnoses of EOFAD from Mainland China. Subsequently, a hexanucleotide repeat expansion in C9orf72 was detected in all patients. Four novel mutations in PSEN1 (p.A434T, p.I167del, p.F105C, and p.L248P) were identified in 4 respective families, and 1 previously recognized pathogenic mutation in APP (p.V717I) was detected in another 2 unrelated families. The PSEN2 mutation and pathogenic repeat expansions of C9orf72 were not detected in all patients. To the best of our knowledge, this is the first cohort report of a causative gene screen in patients with EOFAD in Mainland China. The analysis of the genetic-clinical correlations in this cohort supports the idea that the clinical phenotype might be influenced by specific genetic defects.

Polygenic Analysis of Late-Onset Alzheimer's Disease from Mainland China.

Recently, a number of single nucleotide polymorphisms (SNPs) were identified to be associated with late-onset Alzheimer disease (LOAD) through genome-wide association study data. Identification of SNP-SNP interaction played an important role in better understanding genetic basis of LOAD. In this study, fifty-eight SNPs were screened in a cohort of 229 LOAD cases and 318 controls from mainland China, and their interaction was evaluated by a series of analysis methods. Seven risk SNPs and six protective SNPs were identified to be associated with LOAD. Risk SNPs included rs9331888 (CLU), rs6691117 (CR1), rs4938933 (MS4A), rs9349407 (CD2AP), rs1160985 (TOMM40), rs4945261 (GAB2) and rs5984894 (PCDH11X); Protective SNPs consisted of rs744373 (BIN1), rs1562990 (MS4A), rs597668 (EXOC3L2), rs9271192 (HLA-DRB5/DRB1), rs157581 and rs11556505 (TOMM40). Among positive SNPs presented above, we found the interaction between rs4938933 (risk) and rs1562990 (protective) in MS4A weakened their each effect for LOAD; for three significant SNPs in TOMM40, their cumulative interaction induced the two protective SNPs effects lost and made the risk SNP effect aggravate for LOAD. Finally, we found rs6656401-rs3865444 (CR1-CD33) pairs were significantly associated with decreasing LOAD risk, while rs28834970-rs6656401 (PTK2B-CR1), and rs28834970-rs6656401 (PTK2B-CD33) were associated with increasing LOAD risk. In a word, our study indicates that SNP-SNP interaction existed in the same gene or cross different genes, which could weaken or aggravate their initial single effects for LOAD.

The role of exosomes in the pathogenesis of Alzheimer’ disease

Exosomes are small vesicles secreted by most cell types including neurons that function in intercellular communication through transfer of their cargo or encapsulate and eliminate unnecessary cellular components and therefore have a broad impact on nerve development, activation and regeneration. In addition, exosomes have been observed to be involved in spreading pathological misfolded proteins, thereby leading to the onset and propagation of disease. Alzheimer disease (AD) is the most common form of dementia and characterized by two types of lesions: amyloid plaques and neurofibrillary tangles. Accumulating evidence has demonstrated that exosomes are associated with amyloid precursor (APP) and Tau proteins and play a controversial role in Alzheimer’s disease process. In this review, we will discuss the role of exosomes in the metabolism and secretion of APP and Tau proteins and their subsequent impact on AD pathogenesis.

Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China

Sir, Data recently published in Brain indicate that the CHCHD10 gene (NM_213720.2) plays an important role in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Bannwarth et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Dols-Icardo et al. , 2015; Marroquin et al. , 2015). The CHCHD10 gene is located on chromosome 22q.11.23 and encodes a protein enriched at cristae junctions in mitochondria. Mutations in this gene cause mitochondrial dysfunction, which leads to disease. The study is the first report proposing that mitochondrial dysfunction contributes to the pathogenesis of ALS and FTD. The prevalence of the CHCHD10 mutation has been reported in a number of nationalities, including German (2.3%), French (2.6%), Spanish (0.68%) and Italian (1%) populations (Chaussenot et al. , 2014; Muller et al. , 2014; Chio et al. , 2015; Dols-Icardo et al. , 2015). However, no mutation analysis has been performed in Asian populations, and most variants have been on the ALS or ALS-FTD spectrum. Here, we present data showing that the CHCHD10 mutation is common in patients with the pure FTD phenotype in China. Patients with ALS ( n = 165) and FTD ( n = 65) were recruited at the outpatient clinic of Xiangya Hospital, China. The patients with ALS did not have mutations in SOD1 , FUS , C9orf72 and TARDBP . Additionally, the patients with FTD did not have any variants of MAPT , GRN and C9orf72 . We screened all of the exons in the CHCHD10 gene using Sanger sequencing. The analyses also included 500 unaffected individuals with matched geographical ancestry as healthy controls. This study was approved by the ethics committee of Xiangya Hospital, Central South University in China. …

The APOE ε2 allele may decrease the age at onset in patients with spinocerebellar ataxia type 3 or Machado-Joseph disease from the Chinese Han population

Polymorphism of the apolipoprotein E (APOE) gene has been defined as a modifying factor for age at onset (AO) in neurodegenerative disorders. The AO of spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3 or MJD) is inversely correlated with expanded CAG repeat lengths in the ATXN3 gene; however, AO is only partially explained by the expanded CAG repeats. We performed a case-control study to explore whether APOE genotypes play a role in AO of SCA3 or MJD from the Chinese Han population. The APOE genotypes were analyzed in an independent cohort of 155 patients with SCA3 or MJD and 191 controls both from Mainland China. Our study demonstrated that SCA3 or MJD patients experienced an earlier onset if they were carriers of APOE ε2 allele, which decreased the AO by nearly 4 years. This study may also reconfirm the effect of the APOE gene on SCA3 or MJD patients from different races and indicated that certain APOE alleles might be genetic modifiers for AO in SCA3 or MJD.

Modeling Alzheimer’s Disease with Induced Pluripotent Stem Cells: Current Challenges and Future Concerns

Alzheimers disease (AD) is the most prevalent type of dementia and its pathology is characterized by deposition of extracellular β-amyloid plaques, intracellular neurofibrillary tangles, and extensive neuron loss. While only a few familial AD cases are due to mutations in three causative genes (APP, PSEN1, and PSEN2), the ultimate cause behind the rest of the cases, called sporadic AD, remains unknown. Current animal and cellular models of human AD, which are based on the Aβ and tau hypotheses only, partially resemble the familial AD. As a result, there is a pressing need for the development of new models providing insights into the pathological mechanisms of AD and for the discovery of ways to treat or delay the onset of the disease. Recent preclinical research suggests that stem cells can be used to model AD. Indeed, human induced pluripotent stem cells can be differentiated into disease-relevant cell types that recapitulate the unique genome of a sporadic AD patient or family member. In this review, we will first summarize the current research findings on the genetic and pathological mechanisms of AD. We will then highlight the existing induced pluripotent stem cell models of AD and, lastly, discuss the potential clinical applications in this field.

Identification of CHCHD10 Mutation in Chinese Patients with Alzheimer Disease

CHCHD10 gene has been identified to be associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Considering the clinical phenotype and pathology characterization were overlapped between FTD and Alzheimer disease (AD), and so far, no systematic analysis of CHCHD10 mutation was conducted in patients with AD in Asian population. Therefore, we screened of all exons in CHCHD10 in a cohort of 484 AD patients (60 with family history) from Mainland China. A heterozygous variant p.A35D (c.104C>A), previously reported in a patient with FTD in Italian population, was identified in a female patient with sporadic LOAD. The age at onset of mutation carrier was 86, presented as typical amnestic dementia. The mutation was found to be deleterious according to in silico predictions and excluded in 500 ethnically and geographically matched controls. Our finding revealed the clinical manifestations of variant p.A35D (c.104C>A) in a LOAD case and indicated that CHCHD10 mutation was presented in different types of dementia.