Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease

Schmidt, Vanessa; Baum, Katharina; Lao, Angelyn R.; Rateitschak, Katja; Schmitz, Yvonne; Teichmann, Anke; Wiesner, Burkhard; Petersen, Claus Munck; Nykjaer, Anders; Wolf, Jana; Wolkenhauer, Olaf; Willnow, Thomas E.

doi:10.1038/emboj.2011.352

Cited by 70 publications

(92 citation statements)

References 38 publications

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“…To more rigorously test the relevance of PACS1 for SORLA transport in neurons, we established a novel cell model by using the neuroblastoma cell line SH-SY5Y, which stably overexpresses the human SORLA and APP695 transgenes (SY5Y-A/S). SH-SY5Y cells express low levels of endogenous SORLA, but these levels are negligible when SORLA transgenes are overexpressed (21). When transiently transfected with a siRNA directed against endogenous PACS1 (without PACS1), expression of the adaptor was strongly reduced compared to that in SY5Y-A/S cells transfected with a scrambled control siRNA (with PACS1) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Burgert

Schmidt

Çağlayan

et al. 2013

Molecular and Cellular Biology

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c Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into A␤ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down A␤. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

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Section: Resultsmentioning

confidence: 99%

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Burgert

Schmidt

Çağlayan

et al. 2013

Molecular and Cellular Biology

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“…Willnow and colleagues ruled out a role for SORLA in retrograde transport of internalized APP but proposed an alternate model in which SORLA acts as a retention factor for APP at the Golgi, impeding its exit and subsequent sorting to the plasma membrane and endocytic organelles (4). T en, using inducible SORLA expression and siRNA knockdown combined with mathematical modeling of APP processing, they proposed yet another model in which SORLA prevents APP oligomerization, thus reducing the ef ciency of APP processing by α-secretase and BACE1 (8). Alternatively, Lah and colleagues have suggested that SORLA reduces BACE1 processing of APP and Aβ production by escorting APP to the endocytic recycling compartment and away from early and late endosomes where internalized APP undergoes amyloidogenic processing (9).…”

Section: Sorla Modulates App Processingmentioning

confidence: 96%

Sorting the Role of SORLA in Alzheimer’s Disease

Buggia-Prévot

Wang

2014

Sci. Transl. Med.

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“…S6). A peptide containing this sequence (termed Ab [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] bound to the SORLA VPS10P domain with a concentration dependency indistinguishable from that of Ab 40 (Fig. 6B, diamond symbols).…”

Section: Sorla Binds To Soluble Ab Through Its Vps10p Domainmentioning

confidence: 99%

Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

et al. 2014

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SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA's Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

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Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease

Cited by 70 publications

References 38 publications

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Sorting the Role of SORLA in Alzheimer’s Disease

Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

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