SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

Mehmedbasic, Arnela; Christensen, Sofie K.; Nilsson, Jonas; Rüetschi, Ulla; Gustafsen, Camilla; Poulsen, Annemarie Svane Aavild; Rasmussen, Rikke Wehner; Fjorback, Anja Nawarecki; Larson, Göran; Andersen, Olav M.

doi:10.1074/jbc.m114.619940

Cited by 44 publications

(44 citation statements)

References 75 publications

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“…This was achieved by using a SORL1 antibody, ab190684, directed towards the LDLR class A repeat region previously reported to be necessary for interaction with APP [17] . In control individuals ( n = 4), the co-localization between SORL1 and APP was low in all individuals but one.…”

Section: Resultsmentioning

confidence: 99%

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Thonberg

Chiang

Lilius

et al. 2017

acta neuropathol commun

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Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0441-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Thonberg

Chiang

Lilius

et al. 2017

acta neuropathol commun

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“…However, the evidence shown here suggests that the variants identified in the EOAD families, SORL1 T588I and T2134, weaken the interaction of SORL1 with FL-APP. This can culminate in excessive APP accumulating at the cell surface either due to failure of the mutant SORL1 to slow trafficking of APP to the cell surface 39 or failure of mutant SORL1 to retrieve FL-APP into the retromer-recycling endosome pathway. 3,4,11,27,32–38 Our result agrees with prior work which suggests that some SORL1 mutants cause reduced trafficking of the mutant SORL1 protein from the endoplasmic reticulum (ER)/Golgi network to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanism for the reduced binding of T588I is unclear, but may relate to subtle changes in the fold of the extracellular domain of SORL1 such that putative APP-binding sites in VPS10 and/or in complement type repeat domains. 39,40 Crucially, while they may have different underlying molecular mechanisms, the net effect of both mutations is the same.…”

Section: Discussionmentioning

confidence: 99%

SORL1 mutations in early- and late-onset Alzheimer disease

et al. 2016

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Objective:To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (SORL1) gene.Methods:We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations.Results:SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking.Conclusions:The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation.

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“…The prevalent model of sorLA function in relation to AD is as sorting receptor for APP, in particular working as an intracellular gate keeper that determines APP exit from the Golgi whereby sorLA activity decreases Aβ production 20,36,37 . Additionally, sorLA in concert with the retromer complex is also reported to assist APP escape from amyloidogenic processing in the endosomal system [38][39][40] .…”

mentioning

confidence: 99%

Mutants of Metal Binding Site M1 in APP E2 Show Metal Specific Differences in Binding of Heparin but Not of sorLA

et al. 2015

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The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease (AD) and appear to be essential for neuronal development and cell homeostasis. Proteolytic processing of APP and its physiological function depend on its interaction with heparin and are influenced by the binding of metal ions and sorLA. We created various mutations of metal binding site M1 residing within the extracellular E2 domain of APP. Using isothermal titration calorimetry and circular dichroism spectroscopy, we analyzed the binding of Cu(2+) and Zn(2+) to APP E2 and identified two mutations that are most suited for functional studies to dissect ion specific effects of metal binding. The H313A mutation abrogates only copper-based effects, whereas the H382A mutation weakens any metal binding at M1 of APP E2. Subsequently, we tested the effect of Cu(2+) and Zn(2+) on the binding of heparin and sorLA to APP E2 using a chromatographic technique and surface plasmon resonance. We show that Zn(2+) and to a larger degree also Cu(2+) enhance the binding of heparin to APP E2, consistent with an extracellular regulation of the function of APP by both metal ions. In contrast, neither ion seemed to affect the interaction between APP E2 and sorLA. This supports an intracellular interaction between the latter two partners that would not sense extracellular variations of metal ions upon synaptic activity.

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SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

Cited by 44 publications

References 75 publications

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

SORL1 mutations in early- and late-onset Alzheimer disease

Mutants of Metal Binding Site M1 in APP E2 Show Metal Specific Differences in Binding of Heparin but Not of sorLA

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