The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Joseph H Lee - One of the best experts on this subject based on the ideXlab platform.
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coding mutations in SORL1 and alzheimer disease
Annals of Neurology, 2015Co-Authors: Badri N Vardarajan, Joseph H Lee, Yalun Zhang, Christopher Bohm, Rong Cheng, Christiane Reitz, Mahdi Ghani, Dolly Reyesdumeyer, Yufeng ShenAbstract:Objective Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the mechanism been established. The study was undertaken to identify functional SORL1 mutations in patients with LOAD. Methods This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in SORL1 were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for Aβ40 and Aβ42 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined. Results Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with minor allele frequency (MAF) < 1% and 1 common variant (rs2298813-A528T) with MAF = 14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, although in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway. Interpretation Common and rare variants in SORL1 elevate the risk of LOAD by directly affecting APP processing, which in turn can result in increased Aβ40 and Aβ42 secretion. Ann Neurol 2015;77:215–227
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the neuronal sortilin related receptor gene SORL1 and late onset alzheimer s disease
Current Neurology and Neuroscience Reports, 2008Co-Authors: Joseph H Lee, Sandra Barral, Christiane ReitzAbstract:Recent studies indicate that two clusters of single nucleotide polymorphisms in the neuronal sortilin-related receptor gene (SORL1) are causally associated with late-onset Alzheimer’s disease (AD). At the cellular level, SORL1 is thought to be involved in intracellular trafficking of amyloid precursor protein. When this gene is suppressed, toxic amyloid β production is increased, and high levels of amyloid β are associated with a higher AD risk. Extending the cellular findings, gene expression studies show that SORL1 is differentially expressed in AD patients compared with controls. Furthermore, several genetic studies have identified allelic and haplotypic SORL1 variants associated with late-onset AD, and these variants confer small to modest risk of AD. Taken together, the evidence for SORL1 as a causative gene is compelling. However, putative variants have not yet been identified. Further research is necessary to determine its utility as a diagnostic marker of AD or as a target for new therapeutic approaches.
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association between SORL1 and alzheimer s disease in a genome wide study
Neuroreport, 2007Co-Authors: Yan Meng, Joseph H Lee, Peter St Georgehyslop, Richard Mayeux, Rong Cheng, Lindsay A FarrerAbstract:Several studies [1–3] have reported an association of Alzheimer disease (AD) with polymorphic markers in SORL1. Data from a recently published genome wide association study in AD [4] have been made publically available. We tested the association of AD with SORL1 in this dataset (TGEN), which included 31 SORL1 SNPs, 8 of which overlapped the original study [1]. Six SNPs, near the 3′ region of SORL1 containing SNPs which were strongly associated with AD in previous studies, showed significant association in the TGEN dataset. These results provide an independent replication of the association between AD and SORL1.
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association between genetic variants in sortilin related receptor 1 SORL1 and alzheimer s disease in adults with down syndrome
Neuroscience Letters, 2007Co-Authors: Joseph H Lee, Maruit Chulikavit, Deborah Pang, Warren B Zigman, Wayne Silverman, Nicole SchupfAbstract:Abstract Recent reports have suggested that variants in the sortilin-related receptor gene ( SORL1 ) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African–American and Isreali–Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45–70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08–0.86; and HR = 0.40, 95% CI: 0.16–0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.
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the association between genetic variants in SORL1 and alzheimer disease in an urban multiethnic community based cohort
JAMA Neurology, 2007Co-Authors: Joseph H Lee, Ekaterina Rogaeva, Rong Cheng, Lindsay A Farrer, Nicole Schupf, Jennifer J Manly, Rafael Lantigua, Yaakov Stern, Yosuke Wakutani, Peter St GeorgehyslopAbstract:Objective To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population. Design We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older. Setting Northern Manhattan, NY. Participants There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%). Main Outcome Measures We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate. Results Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5′ region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3′ region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3′ region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 ( P = .035), which was significantly associated with AD in the North European white individuals in our previous report. Conclusions This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1 . Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
Michael Lardelli - One of the best experts on this subject based on the ideXlab platform.
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brain transcriptome analysis of a protein truncating mutation in sortilin related receptor 1 associated with early onset familial alzheimer s disease indicates early effects on mitochondrial and ribosome function
Journal of Alzheimer's Disease, 2021Co-Authors: Karissa Barthelson, Morgan Newman, Stephen M Pederson, Michael LardelliAbstract:Background The early cellular stresses leading to Alzheimer's disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.
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brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial alzheimer s disease
Molecular Brain, 2020Co-Authors: Karissa Barthelson, Stephen Pederson, Morgan Newman, Michael LardelliAbstract:To prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in SORL1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains, comparing wild type fish with their siblings heterozygous for EOfAD-like or putatively loss-of-function mutations in SORL1, or transheterozygous for these mutations. Differential gene expression analysis identified a small number of differentially expressed genes due to the SORL1 genotypes. We also performed enrichment analysis on all detectable genes to obtain a more complete view on changes to gene expression by performing three methods of gene set enrichment analysis, then calculated an overall significance value using the harmonic mean p-value. This identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to SORL1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type SORL1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.
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transcriptome analysis of a protein truncating mutation in sortilin related receptor 1 associated with early onset familial alzheimer s disease indicates effects on mitochondrial and ribosome function in young adult zebrafish brains
bioRxiv, 2020Co-Authors: Karissa Barthelson, Morgan Newman, Stephen M Pederson, Michael LardelliAbstract:The early cellular stresses which eventually lead to Alzheimer's disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid {beta} A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid {beta} (A{beta}) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.
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brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial alzheimers disease
bioRxiv, 2020Co-Authors: Karissa Barthelson, Stephen Pederson, Morgan Newman, Michael LardelliAbstract:Background: To prevent or delay the onset of Alzheimers disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. Methods: To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in SORL1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations in SORL1 or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions. Results: We identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to SORL1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type SORL1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Conclusions: Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.
Giulia Monti - One of the best experts on this subject based on the ideXlab platform.
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in vivo evidence that SORL1 encoding the endosomal recycling receptor sorla can function as a causal gene in alzheimer s disease
bioRxiv, 2021Co-Authors: Olav M Andersen, Giulia Monti, Anne Mette G Jensen, Nikolaj Boegh, Anne M Landau, Gro Grunnet Ploeen, Benedicte Parm Ulhoei, Jens R Nyengaard, Kirsten Rosenmay Jacobsen, Margarita Melnikova JoergensenAbstract:The few established causal genes in Alzheimer's disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Goettingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in A{beta} and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.
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expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with alzheimer s disease
Acta neuropathologica communications, 2021Co-Authors: Giulia Monti, Mads Kjolby, Mariet Allen, Anne Mette G Jensen, Juliane Reiche, Peter Loof Moller, Raquel Comaposadabaro, Bartlomiej E Zolkowski, Carmen Vieira, Margarita Melnikova JorgensenAbstract:SORL1 is strongly associated with both sporadic and familial forms of Alzheimer’s disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.
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20 years anniversary for sorla SORL1 1996 2016
Receptors and clinical investigation, 2019Co-Authors: Giulia Monti, Olav M AndersenAbstract:SORLA is a sorting receptor known to control the intracellular trafficking of the amyloid precursor protein, which impaired pathway has a central role in the development of Alzheimer’s disease (AD). Recently, genetic analyses confirmed the casual role for SORLA in AD, as coding variants and single nucleotide polymorphisms of SORL1 (gene encoding SORLA) were identified in individuals affected by early-onset AD and late-onset AD, respectively. However, many other different types of ligands were found to target the receptor, thus strongly indicating that SORLA can exert multifunctional activities. In the current review, we provide an overview of the multi-ligand properties of SORLA, showing how this complex receptor is involved in a variety of biological functions.
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an alternative transcript of the alzheimer s disease risk gene SORL1 encodes a truncated receptor
Neurobiology of Aging, 2018Co-Authors: Jenny Blechingberg, Annemarie Svane Aavild Poulsen, Mads Kjolby, Giulia Monti, Mariet Allen, Anne Kathrine Ivarsen, Sarah Lincoln, Gangadaar Thotakura, Christian Bjerggaard VaegterAbstract:Abstract SORL1 encodes a 250-kDa protein named sorLA, a functional sorting receptor for the amyloid precursor protein (APP). Several single nucleotide polymorphisms of the gene SORL1, encoding sorLA, are genetically associated with Alzheimer's disease (AD). In the existing literature, SORL1 is insufficiently described at the transcriptional level, and there is very limited amount of functional data defining different transcripts. We have characterized a SORL1 transcript containing a novel exon 30B. The transcript is expressed in most brain regions with highest expression in the temporal lobe and hippocampus. Exon 30B is spliced to exon 31, leading to a mature transcript that encodes an 829 amino acid sorLA receptor. This receptor variant lacks the binding site for APP and is unlikely to function in APP sorting. This transcript is expressed in equal amounts in the cerebellum from AD and non-AD individuals. Our data describe a transcript that encodes a truncated sorLA receptor, suggesting novel neuronal functions for sorLA and that alternative transcription provides a mechanism for SORL1 activity regulation.
Karissa Barthelson - One of the best experts on this subject based on the ideXlab platform.
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brain transcriptome analysis of a protein truncating mutation in sortilin related receptor 1 associated with early onset familial alzheimer s disease indicates early effects on mitochondrial and ribosome function
Journal of Alzheimer's Disease, 2021Co-Authors: Karissa Barthelson, Morgan Newman, Stephen M Pederson, Michael LardelliAbstract:Background The early cellular stresses leading to Alzheimer's disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.
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brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial alzheimer s disease
Molecular Brain, 2020Co-Authors: Karissa Barthelson, Stephen Pederson, Morgan Newman, Michael LardelliAbstract:To prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in SORL1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains, comparing wild type fish with their siblings heterozygous for EOfAD-like or putatively loss-of-function mutations in SORL1, or transheterozygous for these mutations. Differential gene expression analysis identified a small number of differentially expressed genes due to the SORL1 genotypes. We also performed enrichment analysis on all detectable genes to obtain a more complete view on changes to gene expression by performing three methods of gene set enrichment analysis, then calculated an overall significance value using the harmonic mean p-value. This identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to SORL1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type SORL1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.
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transcriptome analysis of a protein truncating mutation in sortilin related receptor 1 associated with early onset familial alzheimer s disease indicates effects on mitochondrial and ribosome function in young adult zebrafish brains
bioRxiv, 2020Co-Authors: Karissa Barthelson, Morgan Newman, Stephen M Pederson, Michael LardelliAbstract:The early cellular stresses which eventually lead to Alzheimer's disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid {beta} A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid {beta} (A{beta}) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.
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brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial alzheimers disease
bioRxiv, 2020Co-Authors: Karissa Barthelson, Stephen Pederson, Morgan Newman, Michael LardelliAbstract:Background: To prevent or delay the onset of Alzheimers disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. Methods: To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in SORL1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations in SORL1 or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions. Results: We identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to SORL1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type SORL1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Conclusions: Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.
Zhanjun Zhang - One of the best experts on this subject based on the ideXlab platform.
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SORL1 rs1699102 polymorphism modulates age related cognitive decline and gray matter volume reduction in non demented individuals
European Journal of Neurology, 2017Co-Authors: Caishui Yang, Dongfeng Wei, Kewei Chen, Zhanjun ZhangAbstract:Background and purpose SORL1 rs1699102 is associated with the risk of late-onset Alzheimer's disease. However, the effects of this single nucleotide polymorphism on cognition and brain structure during normal aging are unclear. This study aimed to examine the effects of the rs1699102 polymorphism on age-related cognitive decline and cortical gray matter reduction in the Chinese Han population. Methods A total of 780 non-demented adults completed a battery of neuropsychological tests. High-resolution T1-weighted structural magnetic resonance imaging data from 89 of these subjects were also collected using a Siemens Trio 3.0 Tesla scanner. Results The T allele carriers displayed an accelerated age-related change in episodic memory and processing speed tests relative to the CC genotype. A similar pattern was observed in the age-related gray matter volume (GMV) reduction of the right middle temporal pole. The GMV in this region was significantly positively correlated with the episodic memory scores. Conclusions The SORL1 gene rs1699102 polymorphism has been found to be associated with age-related cognitive decline and GMV reduction of the right middle temporal pole in older adults. These findings elucidate how the SORL1 variants shape the neural system to modulate age-related cognitive decline and support the hypothesis that SORL1 may represent a candidate gene for late-onset Alzheimer's disease.
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sex moderates the effects of the SORL1 gene rs2070045 polymorphism on cognitive impairment and disruption of the cingulum integrity in healthy elderly
Neuropsychopharmacology, 2015Co-Authors: Ying Liang, Kewei Chen, Zhanjun Zhang, Ni Shu, Junying ZhangAbstract:Sex Moderates the Effects of the SORL1 Gene rs2070045 Polymorphism on Cognitive Impairment and Disruption of the Cingulum Integrity in Healthy Elderly
