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- W2896250263 abstract "SORL1 is an established risk gene for Alzheimer's disease (AD) that encodes the neuronal sortilin related receptor SORLA. Genome-wide association studies showed that SORL1 is associated with late-onset AD through several single nucleotide polymorphisms clustered in two independent haplotype blocks in the 5′ and 3′ regions of the gene, respectively. Moreover, SORL1 loss-of-functions variants were also recently identified in patients with early-onset AD providing direct evidence that SORL1 defects are causative of the disease. qPCR was used to quantify the expression of a novel SORL1 splice variant in human tissues. The cellular localization of transcript and translation product was investigated by in-situ hybridization and immunohistochemistry, respectively. Characterization of the novel receptor protein was performed by immunocytochemistry, deglycosylation, and pulse-chase maturation studies. We here describe a SORL1 transcript containing a novel exon located between exon 38 and exon 39, named 38B, that is located within the 3’ risk haploblock region. We demonstrated the presence of this novel SORL1 transcript in various human tissues, showing the strongest expression in cerebellum. In addition, we found that SORL1-38B is reduced by >50% in the cerebellum of 25 AD patients compared to 25 control cerebellum samples. We observed a strong cellular retention of this novel variant despite the receptor protein lacks a transmembrane segment, but confirm the production of a stable translation product from this transcript. Within the human cerebellum SORL1-38B is mainly found in the soma and dendrites of Purkinje cells. The reduction of SORL1-38B levels in AD brain provides clues of a potential protective role for this alternative transcript in the onset of AD, and the specific cerebellar expression might be related to new independent physiological functions of this variant. Accordingly, the novel SORL1 transcript represents a new candidate AD risk factor, and thus qualifies for further investigations to elaborate its impacts on AD pathology." @default.
- W2896250263 created "2018-10-26" @default.
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- W2896250263 date "2018-07-01" @default.
- W2896250263 modified "2023-10-16" @default.
- W2896250263 title "P4‐259: A NOVEL <i>SORL1</i> TRANSCRIPT THAT IS DOWNREGULATED IN ALZHEIMER'S DISEASE" @default.
- W2896250263 doi "https://doi.org/10.1016/j.jalz.2018.07.081" @default.
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