The Vps10p-domain receptor family

Hermey, Guido

doi:10.1007/s00018-009-0043-1

Cited by 178 publications

(164 citation statements)

References 94 publications

(174 reference statements)

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“…8 Specifically, the p.Gly511Arg mutation targets a highly conserved residue present in proteins containing a VPS10p domain. 9 Finally, the p.Gly1681Asp mutation lies in the less conserved fibronectin cluster that contains six fibronectin type III repeats.…”

Section: Resultsmentioning

confidence: 99%

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Pottier

Hannequin²,

Coutant³

et al. 2012

Mol Psychiatry

256

229

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Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n = 1) or missense (n = 4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

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Section: Resultsmentioning

confidence: 99%

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Pottier

Hannequin²,

Coutant³

et al. 2012

Mol Psychiatry

256

229

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“…For SorCS1, it is possible that the leucine-rich domain also contributes to the binding of APP. However, the limited sequence similarity between the VPS10p receptors might explain why APP only binds to some of the members via the VPS10p domains (54). The unique binding of APP to the SorLA CR-domains might explain the different roles of SorLA, sortilin, and SorCS1 in APP sorting (29,53).…”

Section: Discussionmentioning

confidence: 99%

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

Mehmedbasic

Christensen

Nilsson

et al. 2015

Journal of Biological Chemistry

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Background: SorLA binds APP and decreases the production of A␤; however, the molecular mechanisms controlling these processes are poorly understood. Results: We identified CR(5-8) as an APP-binding site in SorLA. Conclusion: The CR-cluster is essential for the SorLA-dependent decrease in APP proteolysis. Significance: Details regarding the function of SorLA in APP metabolism might lead to an understanding of the genetic association of SorLA with Alzheimer disease.

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“…All Vps10p domain family members are highly enriched in neurons of the mammalian brain, and sortilin is particularly enriched in neurons of the temporal cortex (45,46). We began our investigations by analyzing the protein expression of sortilin and other major Vps10p domain family members, including sorCS1 and sorLA, in the temporal cortex of patient-derived post-mortem brain tissue using quantitative Western blot analysis.…”

Section: The Analysis Of Vps10p Domain Family Members In Ad Postmortementioning

confidence: 99%

“…Finally, SorCS1c also contains YXX⌽ and two LL-like motifs. Their function is undetermined (46,49,(51)(52)(53)(54).…”

Section: Mutagenesis Analysis Of Sortilin Reveals Two Cytoplasmic Motmentioning

confidence: 99%

BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin

Finan

Okada

Kim

2011

Journal of Biological Chemistry

102

107

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BACE1 (␤-site ␤-amyloid precursor protein (APP)-cleaving enzyme 1) mediates the first proteolytic cleavage of APP, leading to amyloid ␤-peptide (A␤) production. It has been reported that BACE1 intracellular trafficking, in particular endosometo-TGN sorting, is mediated by adaptor complexes, such as retromer and Golgi-localized ␥-ear-containing ARF-binding proteins (GGAs). Here we investigated whether sortilin, a Vps10p domain-sorting receptor believed to participate in retromer-mediated transport of select membrane cargoes, contributes to the subcellular trafficking and activity of BACE1. Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1-mediated cleavage of APP in cultured cells. In contrast, RNAi suppression of sortilin results in decreased BACE1-mediated cleavage of APP. We also found that sortilin interacts with BACE1 and that a sortilin construct lacking its cytoplasmic domain, which contains putative retromer sorting motifs, remains bound to BACE1. However, expression of this truncated sortilin redistributes BACE1 from the trans-Golgi network to the endosomes and substantially reduces the retrograde trafficking of BACE1. Site-directed mutagenesis and chimera experiments reveal that the cytoplasmic tail of sortilin, but not those from other VPS10p domain receptors (e.g. SorCs1b and SorLA), plays a unique role in BACE1 trafficking. Our studies suggest a new function for sortilin as a modulator of BACE1 retrograde trafficking and subsequent generation of A␤.

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The Vps10p-domain receptor family

Cited by 178 publications

References 94 publications

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

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

BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin

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