Identification of Alzheimer Disease Risk Genotype That Predicts Efficiency of <emph type="ital">SORL1</emph> Expression in the Brain

Abstract

To identify SORL1 risk genotypes that determine receptor protein expression in the human brain. Design: DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively. Setting: Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank. Subjects: Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease. Results: Our studies identified a SORL1 haplotype in the 3Ј gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein. Conclusion: Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.

Genetic Study of Alzheimer’s Disease in Saudi Population

“…Both SORL1 missense p.Ala528Thr and synonymous p.Ser1187Ser variants were reported in HGMD. The p.Ala528Thr was described as diseaseassociated polymorphism with additional supporting functional evidence [26] and p.Ser1187Ser as disease-associated-polymorphism that may alter the gene expression [22]. The SORL1 single nucleotide polymorphisms identified in our study (Supplementary Table 3) were localized in three of SORL1 domains (VPS10, LDLRA and FN3) (Fig.…”

Genetic Study of Alzheimer’s Disease in Saudi Population

“…Both SORL1 missense p.Ala528Thr and synonymous p.Ser1187Ser variants were reported in HGMD. The p.Ala528Thr was described as diseaseassociated polymorphism with additional supporting functional evidence [26] and p.Ser1187Ser as disease-associated-polymorphism that may alter the gene expression [22]. The SORL1 single nucleotide polymorphisms identified in our study (Supplementary Table 3) were localized in three of SORL1 domains (VPS10, LDLRA and FN3) (Fig.…”

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

“…Indeed, we observed reduced SORL1 expression in lymphoblast cells of the p.Gly447Argfs*22 carrier, which increased upon blocking of NMD, indicative of haploinsufficiency. Further, the mode of action of these predicted loss-of-function mutations is in line with the observation of reduced SORL1 expression in post-mortem brain [ 6 ] and in human neuronal stable cell lines [ 1 ] leading to increased amyloid load. In addition, overexpression of SORL1 cDNA showed decreased amyloid-β secretion in induced human neuronal cells [ 54 ].…”

The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan

“…Following consistent evidence in existing literature of a strong and robust LD structure within the 5′ region of SORL1 (specifically the haplotype defined by SNPs 8-10), 17, 40–43 as well as our own findings of near perfect LD within each analyzed sample (rare haplotype group frequencies were prohibitively low (<1%) and only present in the CAMH and ROS/MAP datasets), we chose to analyze one representative SNP across all four samples (SNP9, rs689021).…”

“…Minor allele homozygotes showed reduced mRNA expression during this period, consistent with our findings of reduced microstructural integrity of white matter already present from childhood onward in the Zucker Hillside sample and from late adolescence onward in the CAMH sample. Previous studies have found allelic differences in SORL1 protein 17 and mRNA levels 52 in elderly postmortem brain; however, by using a lifespan approach, we provide the first evidence that the temporal impact of SORL1 risk variants on SORL1 mRNA expression occurs during neurodevelopmental phases of the lifespan, rather than in late-life.…”

Genetic Study of Alzheimer’s Disease in Saudi Population

“…Both SORL1 missense p.Ala528Thr and synonymous p.Ser1187Ser variants were reported in HGMD. The p.Ala528Thr was described as diseaseassociated polymorphism with additional supporting functional evidence [26] and p.Ser1187Ser as disease-associated-polymorphism that may alter the gene expression [22]. The SORL1 single nucleotide polymorphisms identified in our study (Supplementary Table 3) were localized in three of SORL1 domains (VPS10, LDLRA and FN3) (Fig.…”

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

“…Indeed, we observed reduced SORL1 expression in lymphoblast cells of the p.Gly447Argfs*22 carrier, which increased upon blocking of NMD, indicative of haploinsufficiency. Further, the mode of action of these predicted loss-of-function mutations is in line with the observation of reduced SORL1 expression in post-mortem brain [ 6 ] and in human neuronal stable cell lines [ 1 ] leading to increased amyloid load. In addition, overexpression of SORL1 cDNA showed decreased amyloid-β secretion in induced human neuronal cells [ 54 ].…”

The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan

“…Following consistent evidence in existing literature of a strong and robust LD structure within the 5′ region of SORL1 (specifically the haplotype defined by SNPs 8-10), 17, 40–43 as well as our own findings of near perfect LD within each analyzed sample (rare haplotype group frequencies were prohibitively low (<1%) and only present in the CAMH and ROS/MAP datasets), we chose to analyze one representative SNP across all four samples (SNP9, rs689021).…”

“…Minor allele homozygotes showed reduced mRNA expression during this period, consistent with our findings of reduced microstructural integrity of white matter already present from childhood onward in the Zucker Hillside sample and from late adolescence onward in the CAMH sample. Previous studies have found allelic differences in SORL1 protein 17 and mRNA levels 52 in elderly postmortem brain; however, by using a lifespan approach, we provide the first evidence that the temporal impact of SORL1 risk variants on SORL1 mRNA expression occurs during neurodevelopmental phases of the lifespan, rather than in late-life.…”

Genetic Study of Alzheimer’s Disease in Saudi Population

“…Both SORL1 missense p.Ala528Thr and synonymous p.Ser1187Ser variants were reported in HGMD. The p.Ala528Thr was described as diseaseassociated polymorphism with additional supporting functional evidence [26] and p.Ser1187Ser as disease-associated-polymorphism that may alter the gene expression [22]. The SORL1 single nucleotide polymorphisms identified in our study (Supplementary Table 3) were localized in three of SORL1 domains (VPS10, LDLRA and FN3) (Fig.…”

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

“…Indeed, we observed reduced SORL1 expression in lymphoblast cells of the p.Gly447Argfs*22 carrier, which increased upon blocking of NMD, indicative of haploinsufficiency. Further, the mode of action of these predicted loss-of-function mutations is in line with the observation of reduced SORL1 expression in post-mortem brain [ 6 ] and in human neuronal stable cell lines [ 1 ] leading to increased amyloid load. In addition, overexpression of SORL1 cDNA showed decreased amyloid-β secretion in induced human neuronal cells [ 54 ].…”

The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan

“…Following consistent evidence in existing literature of a strong and robust LD structure within the 5′ region of SORL1 (specifically the haplotype defined by SNPs 8-10), 17, 40–43 as well as our own findings of near perfect LD within each analyzed sample (rare haplotype group frequencies were prohibitively low (<1%) and only present in the CAMH and ROS/MAP datasets), we chose to analyze one representative SNP across all four samples (SNP9, rs689021).…”

“…Minor allele homozygotes showed reduced mRNA expression during this period, consistent with our findings of reduced microstructural integrity of white matter already present from childhood onward in the Zucker Hillside sample and from late adolescence onward in the CAMH sample. Previous studies have found allelic differences in SORL1 protein 17 and mRNA levels 52 in elderly postmortem brain; however, by using a lifespan approach, we provide the first evidence that the temporal impact of SORL1 risk variants on SORL1 mRNA expression occurs during neurodevelopmental phases of the lifespan, rather than in late-life.…”