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P4‐260: AGE‐DEPENDENT CHANGES IN HUMAN CORTEX ANTIOXIDANT AND METHYLATION METABOLIC PATHWAYS: IMPLICATIONS AND OPPORTUNITIES FOR ALZHEIMER'S DISEASE RISK REDUCTION
Author(s) -
Deth Richard C.,
Muratore Christina,
Hodgson Nathaniel,
Zhang Yiting,
Trivedi Malav S.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.07.082
Subject(s) - transsulfuration , homocysteine , cystathionine beta synthase , oxidative stress , endocrinology , methylation , methionine synthase , methionine , medicine , glutathione , chemistry , biology , biochemistry , enzyme , gene , amino acid
Background:SORL1 is an established risk gene forAlzheimer’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 50 and 30 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. Methods: qPCR was used to quantify the expression of a novel SORL1 splicevariant inhuman tissues.Thecellular localizationof 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. Results:We here describe a SORL1 transcript containing a novel exon located between exon38 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 cerebellumof 25ADpatients 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. Conclusions: The reduction of SORL1-38B levels in AD brain provides clues of a potential protective role for this alternative transcript in theonset ofAD,and the specific cerebellar expression might be related to new independent physiological functions of this variant. Accordingly, the novel SORL1 transcript represents a new candidateAD risk factor, and thus qualifies for further investigations to elaborate its impacts on AD pathology.