It is great to see the continuation of the work on sorLA. The authors previously found that this protein influences APP shedding and Aβ generation, both under overexpression and knockout conditions. Their new work sheds more light on the underlying molecular mechanisms. In contrast to many soluble, cytoplasmic proteins that can bind APP and alter APP shedding, sorLA is one of very few membrane proteins that have been reported to coimmunoprecipitate with APP. The authors propose that sorLA interferes with complex formation between APP and BACE1. It will be interesting to see how exactly sorLA interacts with APP/C99 and BACE1, and whether the interaction is mediated through the transmembrane domains or through the cytoplasmic domains. Potentially, sorLA may also interact with the other APP secretases, in particular with the ADAM proteases.

View all comments by Stefan Lichtenthaler

This is the latest paper in a series of studies looking at the modifying effect of LR11/SorLA on APP processing. Despite some differences to the previous paper by Andersen and coworkers, this study clearly highlights that increases in LR11/SorLA expression reduce Aβ generation. In further studies, it will be interesting to learn more about the underlying molecular mechanisms and the suitability of LR11 as a drug target.

View all comments by Stefan Lichtenthaler

This study by Böhm et al. is the first to show that the mosaic receptor SorLA/LR11 is a substrate for the γ-secretase complex and undergoes intramembraneous cleavage. The authors convincingly demonstrate that the SorLA carboxy-terminal fragment (SorLA-CTF) is cleaved by γ-secretase, releasing a SorLA β peptide and the SorLA intracellular domain (SorICD). Taken together with previously reported data on metalloprotease-mediated ectodomain shedding of SorLA (Hampe et al., 2000), this processing is reminiscent of the processing of other transmembrane proteins such as Notch and the amyloid precursor protein (APP).

In the case of Notch, the intracellular domain translocates to the nucleus and can regulate transcription. In an analogy to this signaling pathway, the authors of this study provide evidence suggesting that SorICD tagged with EGFP also localizes to the nucleus. However, they observed only a fairly weak transcriptional activation in a luciferase reporter assay. Addressing the typically short lifetime of ICDs produced by γ-secretase, the authors provide indirect evidence...  Read more

This study by Böhm et al. is the first to show that the mosaic receptor SorLA/LR11 is a substrate for the γ-secretase complex and undergoes intramembraneous cleavage. The authors convincingly demonstrate that the SorLA carboxy-terminal fragment (SorLA-CTF) is cleaved by γ-secretase, releasing a SorLA β peptide and the SorLA intracellular domain (SorICD). Taken together with previously reported data on metalloprotease-mediated ectodomain shedding of SorLA (Hampe et al., 2000), this processing is reminiscent of the processing of other transmembrane proteins such as Notch and the amyloid precursor protein (APP).

In the case of Notch, the intracellular domain translocates to the nucleus and can regulate transcription. In an analogy to this signaling pathway, the authors of this study provide evidence suggesting that SorICD tagged with EGFP also localizes to the nucleus. However, they observed only a fairly weak transcriptional activation in a luciferase reporter assay. Addressing the typically short lifetime of ICDs produced by γ-secretase, the authors provide indirect evidence that insulin-degrading enzyme might be responsible for the degradation of SorICD.

SorLA has recently been linked to Alzheimer disease (AD) in several ways: It is normally highly expressed in the brain, but reduced in AD brains (Scherzer et al., 2004); it has been shown to interact with APP and to regulate amyloid-β peptide (Aβ) levels (Andersen et al., 2005; Offe et al. 2006); and it was reported to interact with the β-secretase BACE (Spoelgen et al., 2006). The present paper extends the links between SorLA and AD to include an interaction with γ-secretase. SorLA thus interacts with all of the proteins immediately involved in Aβ generation and may emerge as an important player in the regulation of Aβ production and the progression of AD.

References:
Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci. 2000 Dec;113 Pt 24:4475-85. Abstract

Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. Abstract

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. Epub 2005 Sep 7. Abstract

Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ. The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006 Feb 1;26(5):1596-603. Abstract

Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT. Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci. 2006 Jan 11;26(2):418-28. Abstract

View all comments by James J. Lah
View all comments by Katrin Offe

SorLA—a new substrate for γ-secretase
Sorting protein-related receptor (SorLA) is a neuronal transmembrane protein that received considerable attention as a possible new factor involved in regulation of APP processing. Initially identified as a gene down-regulated in the brains of patients suffering from Alzheimer’s disease (1), detailed cell biological studies by Andersen et al. (2,3) and Offe and coworkers (4) demonstrated that SorLA directly interacts with the amyloid precursor protein (APP) and that it affects intracellular transport and processing of the precursor to the Aβ peptide. In general, increased expression of SorLA in neurons coincides with a reduction in Aβ production while inactivation of the gene in a knockout mouse model increases Aβ formation, suggesting a possible role for this receptor as inhibitor of APP processing and senile plaque formation. A mechanistic model of how SorLA may inhibit amyloidogenic peptide formation was provided by Spoelgen et al., who uncovered a close interaction of SorLA with the β-site APP cleaving enzyme (BACE) inhibiting...  Read more

SorLA—a new substrate for γ-secretase
Sorting protein-related receptor (SorLA) is a neuronal transmembrane protein that received considerable attention as a possible new factor involved in regulation of APP processing. Initially identified as a gene down-regulated in the brains of patients suffering from Alzheimer’s disease (1), detailed cell biological studies by Andersen et al. (2,3) and Offe and coworkers (4) demonstrated that SorLA directly interacts with the amyloid precursor protein (APP) and that it affects intracellular transport and processing of the precursor to the Aβ peptide. In general, increased expression of SorLA in neurons coincides with a reduction in Aβ production while inactivation of the gene in a knockout mouse model increases Aβ formation, suggesting a possible role for this receptor as inhibitor of APP processing and senile plaque formation. A mechanistic model of how SorLA may inhibit amyloidogenic peptide formation was provided by Spoelgen et al., who uncovered a close interaction of SorLA with the β-site APP cleaving enzyme (BACE) inhibiting BACE-APP contact, and hence BACE cleavage of APP (5). Wolfgang Hampe and colleagues now add yet another twist to this story. In this study, they provide evidence that SorLA is a target for intramembrane proteolysis by the γ-secretase complex. Much like APP, SorLA seems to be a substrate of presenilin-dependent proteolytic processing, liberating a short cytoplasmic tail fragment (designated intracellular domain or ICD) that can translocate to the nucleus. As well as with APP, processing of SorLA by γ-secretase requires preceding cleavage of the extracellular domain to produce a short, membrane-anchored receptor fragment that acts as a substrate for the γ-secretase complex. In the case of SorLA, such ectodomain shedding seems to be accomplished by the metalloprotease TACE (7,8). Thus, SorLA is another name on the growing list of membrane proteins that are targets of γ-secretase activity, highlighting the overall biological importance of regulated intramembrane proteolysis. In targets such as APP or Notch, the ICD acts as transcriptional regulator transducing signals from plasma membrane to nucleus. So far, no firm evidence has been provided as to the physiological significance of SorLA cleavage, and whether or not cleavage affects its function as negative regulator of APP processing and Aβ formation. Nevertheless, this new study further emphasizes the importance of this neuronal receptor that functionally interacts with several key components of the amyloidogenic pathway including APP, BACE, and γ-secretase.

References:
1. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. Abstract

2. Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT, Cappai R, Willnow TE. Molecular Dissection of the Interaction between Amyloid Precursor Protein and Its Neuronal Trafficking Receptor SorLA/LR11. Biochemistry. 2006 Feb 28;45(8):2618-2628. Abstract

3. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. Epub 2005 Sep 7. Abstract

4. Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ. The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006 Feb 1;26(5):1596-603. Abstract

5. Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT. Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci. 2006 Jan 11;26(2):418-28. Abstract

6. Bohm C, Seibel N, Henkel B, Steiner H, Haass C, Hampe W. SorLA signaling by regulated intramembrane proteolysis. J Biol Chem. 2006 Mar 10; [Epub ahead of print] Abstract

7. Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci. 2000 Dec;113 Pt 24:4475-85. Abstract

8. Hermey G, Sjogaard S, Petersen CM, Nykjaer A, Gliemann J. Tumour necrosis factor-alpha convertase mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J. 2006 Jan 4; [Epub ahead of print] Abstract

View all comments by Thomas Willnow

In this article, Bohm et al. demonstrate that the multifunctional mosaic receptor SorLA can be processed by γ-secretase to generate a SorLA cytoplasmic domain. The cleavage of SorLA is analogous to Notch processing and adds a new receptor to the growing number of γ-secretase substrates.

Of particular interest is the finding that the cytoplasmic domain of SorLA migrates to the nucleus and a reporter gene assay suggests a role of SorLA's cytoplasmic domain in transcriptional regulation.

Although the authors found evidence for a signaling function of SorLA and γ-secretase, it still remains unclear whether the function of the cleavage is mainly to degrade membrane-spanning proteins such as SorLA or whether the γ-secretase initiates signal transduction pathways by generating potential transcription factors.

Since previous studies demonstrated that SorLA levels are reduced in the brain of Alzheimer disease patients, Bohm et al. propose a model in which SorLA might compete with APP for γ-secretase cleavage. The relative absence of the receptor in Alzheimer patients could...  Read more

In this article, Bohm et al. demonstrate that the multifunctional mosaic receptor SorLA can be processed by γ-secretase to generate a SorLA cytoplasmic domain. The cleavage of SorLA is analogous to Notch processing and adds a new receptor to the growing number of γ-secretase substrates.

Of particular interest is the finding that the cytoplasmic domain of SorLA migrates to the nucleus and a reporter gene assay suggests a role of SorLA's cytoplasmic domain in transcriptional regulation.

Although the authors found evidence for a signaling function of SorLA and γ-secretase, it still remains unclear whether the function of the cleavage is mainly to degrade membrane-spanning proteins such as SorLA or whether the γ-secretase initiates signal transduction pathways by generating potential transcription factors.

Since previous studies demonstrated that SorLA levels are reduced in the brain of Alzheimer disease patients, Bohm et al. propose a model in which SorLA might compete with APP for γ-secretase cleavage. The relative absence of the receptor in Alzheimer patients could therefore lead to increased cleavage of APP and to elevated Aβ peptide production in patients.

In addition to the potential role of SorLA as a competitive substrate of γ-secretase, our own studies suggest that SorLA directly influences APP processing by directing APP into compartments that are less favorable for Aβ peptide production. Overall, it is striking that a few APP-influencing proteins share very specific pathways and interaction partners.

View all comments by Robert Spoelgen