SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB). Methods: Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined. Results: We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region. Conclusions: SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS

Als mutations in FUS cause neuronal dysfunction and death in caenorhabditis elegans by a dominant gain-of-function mechanism

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WTFUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions

ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins

Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases

This is the final version of the article. Available from the publisher via the DOI in this record.Open Access funded by Wellcome TrustThe similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.Rita Guerreiro and Jose Bras are supported by Research Fellowships from the Alzheimer's Society. This work was supported in part by a Parkinson's UK Innovation Award (K-1204) in collaboration with the Lewy Body Society and by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee and by an anonymous Foundation. The authors would like to acknowledge Elena Lorenzo for her technical assistance. This study was supported in part by grants from the Spanish Ministry of Science and InnovationSAF2006-10126 (2006–2009) and SAF2010-22329-C02-01 (2011–2013) and SAF2013-47939-R (2013–2015) to Pau Pastor and by the UTE project FIMA to Pau Pastor. They acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Centre. The sample collection and database of the Amsterdam Dementia Cohort was funded by Stichting Dioraphte and Stichting VUMC fonds. Glenda M. Halliday is a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia. For the neuropathologically confirmed samples from Australia, brain tissue was received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia, the University of New South Wales, and the National Health and Medical Research Council of Australia. This study was also partially funded by the Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research, Ontario Research Fund. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (Lorraine Clark), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I. R. Burke), and UL1TR000040 (P.I. H. Ginsberg). Owen A. Ross is supported by the Michael J. Fox Foundation, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by the Mangurian Foundation for Lewy body research. This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology. Some of the tissue samples studies were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by the NIHR UCLH Biomedical Research Centre, the Queen Square Dementia Biomedical Research Unit, the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Hospital, London. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust and the Medical Research Council

Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish

BACKGROUND: Population heterogeneity may be a significant confounding factor hampering detection and verification of late onset Alzheimer's disease (LOAD) susceptibility genes. The Amish communities located in Indiana and Ohio are relatively isolated populations that may have increased power to detect disease susceptibility genes. METHODS: We recently performed a genome scan of dementia in this population that detected several potential loci. However, analyses of these data are complicated by the highly consanguineous nature of these Amish pedigrees. Therefore we applied the Combinatorial Mismatch Scanning (CMS) method that compares identity by state (IBS) (under the presumption of identity by descent (IBD)) sharing in distantly related individuals from such populations where standard linkage and association analyses are difficult to implement. CMS compares allele sharing between individuals in affected and unaffected groups from founder populations. Comparisons between cases and controls were done using two Fisher's exact tests, one testing for excess in IBS allele frequency and the other testing for excess in IBS genotype frequency for 407 microsatellite markers. RESULTS: In all, 13 dementia cases and 14 normal controls were identified who were not related at least through the grandparental generation. The examination of allele frequencies identified 24 markers (6%) nominally (p ≤ 0.05) associated with dementia; the most interesting (empiric p ≤ 0.005) markers were D3S1262, D5S211, and D19S1165. The examination of genotype frequencies identified 21 markers (5%) nominally (p ≤ 0.05) associated with dementia; the most significant markers were both located on chromosome 5 (D5S1480 and D5S211). Notably, one of these markers (D5S211) demonstrated differences (empiric p ≤ 0.005) under both tests. CONCLUSION: Our results provide the initial groundwork for identifying genes involved in late-onset Alzheimer's disease within the Amish community. Genes identified within this isolated population will likely play a role in a subset of late-onset AD cases across more general populations. Regions highlighted by markers demonstrating suggestive allelic and/or genotypic differences will be the focus of more detailed examination to characterize their involvement in dementia

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.Jose Bras, Rita Guerreiro, Lee Darwent, Laura Parkkinen, Olaf Ansorge ... Tamas Revesz ... et al

A comprehensive screening of copy number variability in dementia with Lewy bodies

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.info:eu-repo/semantics/publishedVersio

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation