Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer’s Disease

Barthelson, Karissa; Newman, Morgan; Lardelli, Michael

doi:10.3233/adr-200177

Cited by 29 publications

(25 citation statements)

References 153 publications

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“…We did not observe any gene sets involved in endolysosomal system function to be significantly altered in W1818*/+ brains, despite that SORL1 protein is thought to act, primarily, within the endolysosomal system (reviewed in (11)). Knupp and colleagues (47) showed that complete loss of SORL1 in neurons (and not microglia) derived from human induced pluripotent stem cells (hiPSCs) resulted in early endosome enlargement, a phenomenon previously observed in post mortem EOfAD and LOAD brains (48)(49)(50).…”

Section: No Evidence That Mutation Of Sorl1 Significantly Changes Expmentioning

confidence: 60%

Transcriptome analysis of a protein-truncating mutation insortilin-related receptor 1associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

Barthelson

Pederson

Newman

et al. 2020

Preprint

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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 β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) 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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Section: No Evidence That Mutation Of Sorl1 Significantly Changes Expmentioning

confidence: 60%

Transcriptome analysis of a protein-truncating mutation insortilin-related receptor 1associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

Barthelson

Pederson

Newman

et al. 2020

Preprint

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“…Nevertheless, transcripts of the EOfAD-like allele can still be detected and so, potentially, can be translated to produce a truncated protein that may act in a dominant manner. In humans, SORL1 is alternatively spliced to generate at least five protein-coding transcripts (reviewed in [ 26 ]). The C1478* mutation, which is in exon 32 of the full length human transcript, is predicted to affect all protein-coding transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…These proteins all carry a VPS10 domain with homology to the VPS10P domain found in yeast [ 25 ]. SORL1 also belongs to the low density lipoprotein receptor (LDLR) family of proteins and contains both LDLR class A repeats and LDLR class B repeats (reviewed in [ 26 ]).…”

Section: Introductionmentioning

confidence: 99%

“…The functional role of SORL1 has been investigated mostly in the context of the distribution and processing of APP within cells. SORL1 guides APP throughout the endolysosomal system and is thought to prevent formation of Aβ by promoting recycling of APP (reviewed in [ 26 ]). Mutations in the protein-coding region of SORL1 have been shown to reduce the capacity of the SORL1 protein to bind APP and result in increased levels of Aβ [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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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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“…Early onset familial AD (EOfAD) cases have an age of onset before 65 years, and arise due to mutations in the PRESENILIN genes (PSEN1 and PSEN2), and the genes AMYLOID Β A4 PRECURSOR PROTEIN (AbPP) and SORTILIN-RELATED RECEPTOR 1 (SORL1) (reviewed in [7][8][9]).…”

Section: Introductionmentioning

confidence: 99%

Frameshift and frame-preserving mutations in zebrafishpresenilin 2affect different cellular functions in young adult brains

Barthelson

Pederson

Newman

et al. 2020

Preprint

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BackgroundMutations in PRESENILIN 2 (PSEN2) cause early disease onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon – the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated.MethodsA frameshift mutation (psen2N140fs) and a reading frame-preserving mutation (psen2T141_L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analysed. Bioinformatics techniques were used to predict cellular functions affected by heterozygosity for each mutation.ResultsThe reading frame preserving mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signalling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions.ConclusionA frameshift and frame-preserving mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

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Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer’s Disease

Cited by 29 publications

References 153 publications

Transcriptome analysis of a protein-truncating mutation insortilin-related receptor 1associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

Transcriptome analysis of a protein-truncating mutation insortilin-related receptor 1associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

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

Frameshift and frame-preserving mutations in zebrafishpresenilin 2affect different cellular functions in young adult brains

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