LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor

Laat, Rian de; Meabon, James S.; Wiley, Jesse C.; Hudson, Mark; Montine, Thomas J.; Bothwell, Mark

doi:10.3402/pba.v5.25796

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…Complex formation with LRP, BACE1 and Ran-binding protein 9 (RanBP9), a scaffolding protein involved in trafficking of membrane receptors [240] , reduces APP cell surface localization, and favors internalization of APP and generate Aβ [241, 242] . Similar functional outcome has been proposed for the interaction of APP with lingo proteins [151, 243] , which can form a complex with NgR and p75 [244, 245] . Lingo family of proteins has been associated with growth factor receptor internalization and subsequent proteasomal degradation in other systems [245, 246] .…”

Section: Functional Consequence Of App Internalization On Aβ Clearancesupporting

confidence: 64%

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APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

113

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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Section: Functional Consequence Of App Internalization On Aβ Clearancesupporting

confidence: 64%

“…Knockdown of lingo expression reduces Aβ production, apparently by favoring α-secretase processing of APP. However, overexpression of lingo results in increased lysosomal degradation of APP [243] .…”

Section: Functional Consequence Of App Internalization On Aβ Clearancementioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

113

110

View full text Add to dashboard Cite

show abstract

“…It is also shown that expression of LINGO-1 was down-regulated in AD cortical gray matter [160]. Over-expression of LINGO-1 in cortical neurons significantly reduced APP levels, which supports the hypothesis that LINGO-1 promotes APP degradation and inhibits Aβ generation [159].…”

Section: Endo-lysosomal Autophagy Pathway Failurementioning

confidence: 70%

“…LINGO-1 is predominately expressed in the central nervous system [202]. Experimental reports demonstrated that the physical interaction between LINGO-1 and APP promotes lysosomal degradation of APP, and thereby reduces available APP for amyloidogenic process [159]. It is also shown that expression of LINGO-1 was down-regulated in AD cortical gray matter [160].…”

Section: Endo-lysosomal Autophagy Pathway Failurementioning

confidence: 99%

Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis

Cao

Zhong

Toro

et al. 2019

Neuroscience Letters

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Several lines of evidence have shown that defects in the endo-lysosomal autophagy degradation pathway and the ubiquitin-proteasome system play a role in Alzheimer’s Disease (AD) pathogenesis and pathophysiology. Early pathological changes, such as marked enlargement of endosomal compartments, gradual accumulation of autophagic vacuoles (AVs) and lysosome dyshomeostasis, are well-recognized in AD. In addition to these pathological indicators, many genetic variants of key regulators in the endo-lysosomal autophagy networks and the ubiquitin-proteasome system have been found to be associated with AD. Furthermore, altered expression levels of key proteins in these pathways have been found in AD human brain tissues, primary cells and AD mouse models. In this review, we discuss potential disease mechanisms underlying the dysregulation of protein homeostasis governing systems. While the importance of two major protein degradation pathways in AD pathogenesis has been highlighted, targeted therapy at key components of these pathways has great potential in developing novel therapeutic interventions for AD. Future investigations are needed to define molecular mechanisms by which these complex regulatory systems become malfunctional at specific stages of AD development and progression, which will facilitate future development of novel therapeutic interventions. It is also critical to investigate all key components of the protein degradation pathways, both upstream and downstream, to improve our abilities to manipulate transport pathways with higher efficacy and less side effects.

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“…Receptor tyrosine kinases negatively regulated by LINGO-1 include TrkA, TrkB and TrkC (present results and Fu et al, 2010) and EGFR/ErbB1 (Inoue et al, 2007). Receptor tyrosine kinases are not the only cellular targets of LIG protein-mediated regulation, however, as a C. elegans LRIG ortholog positively regulates signaling by BMP receptors (Gumienny et al 2010) and LINGO-1 enables signaling by NgR/p75 NTR complexes (Mi et al, 2004) and promotes lysosomal degradation of the β-amyloid precursor protein (de Laat et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling

Meabon

Laat

Ieguchi

et al. 2016

Molecular and Cellular Neuroscience

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Neurotrophins, essential regulators of many aspects of neuronal differentiation and function, signal via four receptors, p75, TrkA, TrkB and TrkC. The three Trk paralogs are members of the LIG superfamily of membrane proteins, which share extracellular domains consisting of leucine rich repeat and C2 Ig domains. Another LIG protein, LINGO-1 has been reported to bind and influence signaling of p75 as well as TrkA, TrkB and TrkC. Here we examine the manner in which LINGO-1 influences the function of TrkA, TrkB and TrkC. We report that Trk activation promotes Trk association with LINGO-1, and that this association promotes Trk degradation by a lysosomal mechanism. This mechanism resembles the mechanism by which another LIG protein, LRIG1, promotes lysosomal degradation of receptor tyrosine kinases such as the EGF receptor. We present evidence indicating that the Trk/LINGO-1 interaction occurs, in part, within recycling endosomes. We show that a mutant form of LINGO-1, with much of the extracellular domain deleted, has the capacity to enhance TrkA signaling in PC12 cells, possibly by acting as an inhibitor of Trk down-regulation by full length LINGO-1. We propose that LINGO-1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including TrkA, TrkB and TrkC.

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LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor

Cited by 16 publications

References 30 publications

APP Receptor? To Be or Not To Be

APP Receptor? To Be or Not To Be

Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis

Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling

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