Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia.

BACKGROUND: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. OBJECTIVE: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. METHODS: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. RESULTS: Gene sequencing of SIGMAR1 revealed a rare 3'UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. CONCLUSION: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype.

Mutation analysis of the ECE1 gene in late-onset Alzheimer's disease.

We recently identified a rare coding mutation (R186C) in the ECE2 gene in a late-onset AD (LOAD) family, and demonstrated ECE2 is a risk gene for AD development. ECE1 is a homologous enzyme that shares catalytic activity with ECE2. Although ECE1 has been regarded as a potential candidate gene for AD, few studies have investigated the role of ECE1 variants in patients with AD. In this study, we aimed to investigate rare variants in ECE1 in a cohort of 610 patients with LOAD (age of onset ≥65 years). The summary data of ECE1 variants from ChinaMAP database were used as controls (n = 10,588). We found four rare variants (p.R50W, p.A166=, p.R650Q, and p.P751=) in the patients with sporadic LOAD, while we identified a large number of controls carrying rare variants in ECE1. Moreover, there was no significant association between LOAD and non-synonymous rare damaging variants at the gene level. Our results suggest rare coding variants of ECE1 might not play an important role in AD risk in the Chinese population.

Adult-Onset Neuronal Ceroid Lipofuscinosis With a Novel DNAJC5 Mutation Exhibits Aberrant Protein Palmitoylation.

Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits.

Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population.

As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.

Precision medicine of frontotemporal dementia: from genotype to phenotype.

Frontotemporal dementia (FTD) is the second most common neurodegenerative  cause of early-onset dementia. FTD has an important genetic component contributing to its pathogenic mechanisms. Currently, extensive research on neuroimaging biomarkers and neurochemical biomarkers in FTD is being conducted to address the clinical need for a sensitive and specific diagnostic marker. Here, we review the advances in genetics, biomarkers and treatment of FTD and how this may represent a shift towards precision medicine. To advance the clinical use of precision medicine, big data cohort for genotype/phenotype research and multidisciplinary team approaches are necessary.

Determining association of rho kinase 1 gene polymorphisms with risk of Alzheimer's disease: a multicenter pilot study.

BACKGROUND: In addition to the increasing evidence for a molecular mechanism of rho kinase 1 (ROCK1) in Alzheimer's disease (AD), there are several published studies regarding the relationship between ROCK1 gene polymorphisms and neurological diseases. However, it is unknown whether there is an association between the polymorphisms of ROCK1 and AD. We sought to identify the potential association between ROCK1 gene polymorphisms and AD in the Chinese Han population. METHODS: A total of 295 patients with AD and 206 healthy controls from multiple centers were enrolled in this study. Three single-nucleotide polymorphisms (SNPs) (rs35996865, rs11873284, and rs2127958) in ROCK1 gene were analyzed using Sanger sequencing. RESULTS: We did not find any significant differences between AD and control groups with regards to the frequency of these three ROCK1 polymorphisms. Further, the three SNP genotype frequencies and allele frequencies did not show significant differences between patients of AD and controls in APOE4-stratified subjects (P>0.01). Additionally, the three SNPs did not show significant differences even when adopting a four-inheritance model by logistic regression. CONCLUSIONS: This is the first multicenter pilot study to evaluate the contribution of ROCK1 genetic variance to AD risk. Our data demonstrated that the ROCK1 gene may not influence the risk of AD by interacting with APOE among Chinese Han people.

Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia.

BACKGROUND: Mutations in microtubule associated protein tau (MAPT), progranulin (GRN), chromosome 9 open-reading frame 72 (C9orf72) and CHCHD10 genes have been reported causing frontotemporal dementia (FTD) in different populations. However, collective analysis of mutations in these four genes in Chinese FTD patients has not been reported yet. METHODS: The aim of this study was to investigate the genetic features of Chinese patients with MAPT, GRN, C9orf72 or CHCHD10 gene mutations in an FTD cohort recruited from multi clinical centers in Shanghai metropolitan areas, China. MAPT, GRN and CHCHD10 genes were analysed by direct sequencing, and C9orf72 hexanucleotide repeat expansion was analysed by repeat-primed PCR in 82 patients with sporadic FTD. The identified gene variants were screened in 400 age matched controls. RESULTS: We found one known pathogenic variant (rs63750959) and one novel mutation (NG_007398.1: g.120962C>T; H299Y) of MAPT gene, one novel variant (c.750C>A; D250E) of GRN gene and two novel mutations in CHCHD10 gene (c.63C>T, no AA change; c.71G>A, P24L). No abnormal C9orf72 gene hexanucleotide repeat expansion was identified in this cohort. Collectively, genetic testing could discover 4.9% sporadic FTD patients with genetic causes. In addition, MAPT and CHCHD10 might be more important genes affecting Chinese with FTD.

Mutation screening of the PRRT2 gene for benign epilepsy with centrotemporal spikes in Chinese mainland population.

Proline-rich transmembrane protein 2 gene (PRRT2) mutations are reported to cause common paroxysmal neurological disorders and show a remarkable pleiotropy. Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common epilepsy syndrome in childhood. It is placed among the idiopathic localization related epilepsies. Recently, it was reported that a girl with a PRRT2 mutation c.649_650insC developed infantile focal epilepsy with bilateral spikes which resembled the rolandic spikes. Hereby we performed a comprehensive genetic mutation screening of PRRT2 gene in a cohort of 53 sporadic BECTS patients. None of the 53 sporadic BECTS patients and other 250 controls carried mutations including c.649_650insC in PRRT2. Our data indicated that the PRRT2 mutations might most likely not be associated with BECTS in Chinese mainland population.

Paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 110 patients.

OBJECTIVE: We aimed to investigate the clinical and genetic features of paroxysmal kinesigenic dyskinesia (PKD) in a large population and to analyze the genotype-phenotype correlation of PKD. METHODS: We analyzed clinical manifestations and conducted PRRT2 screening in 110 patients with PKD. Clinical data were compared between 91 probands with and without PRRT2 mutations. RESULTS: Among the enrolled participants (45 from 26 families, 65 sporadic cases), 8 PRRT2 mutations were detected in 20 PKD families (76.9%) and 14 sporadic cases (21.5%), accounting for 37.4% (34/91) of the study population. Five mutations (c.649dupC, c.649delC, c.487C>T, c.573dupT, c.796C>T) were already reported, while 3 mutations (c.787C>T, c.797G>A, c.931C>T) were undocumented. A patient harboring a homozygous c.931C>T mutation was shown to have inherited the mutation via uniparental disomy. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea, and a positive family history. A good response was shown in 98.4% of the patients prescribed with carbamazepine. CONCLUSIONS: PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea, and a tendency for a family history of PKD. A patient with uniparental disomy resulting in a homozygous c.931C>T mutation is identified in the present study. Carbamazepine is the first-choice drug for patients with PKD, but an individualized treatment regimen should be developed.

Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.

The BAG2 and BAG5 proteins inhibit the ubiquitination of pathogenic ataxin3-80Q.

The expansion of a polyglutamine domain in the protein ataxin3 causes spinocerebellar ataxia type-3 (SCA3). However, there is little information to date about the upstream proteins in the ubiquitin-proteasome system of pathogenic ataxin3-80Q. Here, we report that BAG2 (Bcl-2 associated athanogene family protein 2) and BAG5 (Bcl-2-associated athanogene family protein 5) stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination as determined based on western blotting and co-immunofluorescence experiments. The association of the BAG2 and BAG5 proteins with pathogenic ataxin3-80Q strengthens the important roles of the BAG family in neurodegenerative diseases.

BAG5 protects against mitochondrial oxidative damage through regulating PINK1 degradation.

Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism, and loss of the stability of PINK1 may also contribute to sporadic Parkinson's disease (PD). Degradation of PINK1 occurs predominantly through the ubiquitin proteasome system (UPS), however, to date, few of the proteins have been found to regulate the degradation of PINK1. Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. We showed that BAG5 stabilized PINK1 by decreasing the ubiquitination of PINK1. Interestingly, BAG5 rescued MPP(+)- and rotenone-induced mitochondria dysfunction by up-regulating PINK1 in vitro. In PINK1-null mice and MPTP-treated mice, BAG5 significantly increased in the substantia nigra pars compacta (SNpc) although PINK1 was decreased. Our findings indicated that BAG5, as a key protein to stabilize PINK1, is a promising therapeutic tool for preventing mitochondrial dysfunction following oxidative stress.

The BAG2 protein stabilises PINK1 by decreasing its ubiquitination.

Mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). Thus far, little is known about what can regulate the ubiquitin proteasome pathway of PINK1. Here, we report BAG2 (Bcl-2-associated athanogene family protein 2), a member of the BAG family, which directly binds with and stabilises PINK1 by decreasing its ubiquitination. Moreover, we found that BAG2 also binds with the pathogenic R492X PINK1 mutation directly and more tightly. Moreover, BAG2 stabilises the R492X PINK1 mutation by decreasing its ubiquitination to a greater extent than the wild-type species. Our data correlate BAG2 to PINK1 for the first time, strengthening the important role of BAG2 in PD-related neurodegeneration.