Retromers in Alzheimer’s Disease

Siegenthaler, Barbara; Rajendran, Lawrence

doi:10.1159/000335910

Cited by 28 publications

(29 citation statements)

References 107 publications

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“…Moreover, there is increasing realization that perturbed CSC function is linked to a number of human diseases. CSC deficiency plays a role in nonamyloidogenic versus amyloidogenic processing of amyloid precursor protein (APP) (He et al 2005;Small et al 2005;Muhammad et al 2008;Wen et al 2011;Choy et al 2012) and the pathogenesis of Alzheimer's disease (Siegenthaler and Rajendran 2012). In addition, a specific VPS35 mutation, Asp620Asn, has been linked to late-onset autosomal-dominant familial Parkinson's disease (Vilariño-Güell et al 2011;Zimprich et al 2011), the loci for human VPS26A has been genetically associated with type 2 diabetes in South Asians (Kooner et al 2011), and the endosomal transport of various pathogens (Salmonella, Herpesvirus saimiri, Coxiella burnetii, human papillomavirus, Legionella pneumophila) and toxins (Shiga toxin) is also mediated in part by the CSC Popoff et al 2007;Kingston et al 2011;Finsel et al 2013;Lipovsky et al 2013;McDonough et al 2013).…”

Section: The Diversity Of Retromer Function In Cell Function and Orgamentioning

confidence: 99%

Retromer: A Master Conductor of Endosome Sorting

Burd

Cullen

2014

Cold Spring Harbor Perspectives in Biology

384

440

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The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease. We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network.

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Section: The Diversity Of Retromer Function In Cell Function and Orgamentioning

confidence: 99%

Retromer: A Master Conductor of Endosome Sorting

Burd

Cullen

2014

Cold Spring Harbor Perspectives in Biology

384

440

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“…At this time there are several compounds that have been described as retromer inhibitors and retromer activators [40–41]. Invariably, conditions that reduced or inhibited its activity were associated with increased likelihood of neurodegenerative disorders such as alzheimer’s disease due to hyperstimulation of lysosomes and increased degradation of proteins that relied on the retromer for recycling [40], [42]; while activation of the retromer is thought to be beneficial in reversing damage associated with neurodegenerative disorders [41] and [43]. Screening for agents that affect trafficking by the retromer-independent pathway might reveal a novel physiological trafficking pathway involved in recycling of a large number of useful GPCR and hopefully identify novel pharmacological modifiers of GPCR-mediated signaling events, such as those involved in aberrant signaling by cardiac β 1 -AR in heart failure and other circulatory disorders.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel transplantable GPCR recycling motif for drug discovery

Nooh

Mancarella

Bahouth

2016

Biochemical Pharmacology

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β1-adrenergic receptor (β1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The β1-AR like other G protein-couple receptors (GPCR) is endocytosed in response to intense agonist activation. Recycling of the agonist-internalized β1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine312 in the third intracellular loop of the β1-AR. Progressive elongation of the β1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the β1-AR. However, fusing a twenty amino acid peptide derived from the multiple cloning region of the mammalian expression vector pCDNA3 to the C-tail of the β1-AR (β1-AR[+20]) produced a chimeric β1-AR that recycled rapidly and efficiently. The β1-AR[+20] recycled in a type-1 PDZ and phospho-Ser312-independent manner, indicating that this peptide provided a general GPCR recycling signal. Fusing the enhanced yellow fluorescent protein (EYFP) down-stream of β1-AR[+20] generated a β1-AR-EYFP chimera that was expressed on the membrane and recycled efficiently after agonist-induced internalization. This construct trafficked in a PDZ-SNX27/retromer-independent manner. We also fused EYFP to the N-terminus of the β1-AR to created EYFP-WT β1-AR. This construct recycled in PDZ and SNX27/retromer dependent manner. These β1-AR-EYFP constructs would be useful for high throughput screening (HTS) programs to identify new entities that would interfere with the recycling of agonist internalized GPCR that traffic in PDZ-dependent vs. PDZ-independent roadmaps.

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“…The mechanisms underlying the retrieval of the IGF-II receptor overlap significantly with those of proteins involved in the intracellular trafficking of APP and BACE1. More importantly, GGA, PACS1, and retromer complex have been implicated in the control of APP processing (63,(67)(68)(69).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

Wang

Buggia-Prévot

Zavorka

et al. 2015

Molecular and Cellular Biology

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dAmyloid ␤ (A␤) peptides originating from amyloid precursor protein (APP) in the endosomal-lysosomal compartments play a critical role in the development of Alzheimer's disease (AD), the most common type of senile dementia affecting the elderly. Since insulin-like growth factor II (IGF-II) receptors facilitate the delivery of nascent lysosomal enzymes from the trans-Golgi network to endosomes, we evaluated their role in APP metabolism and cell viability using mouse fibroblast MS cells deficient in the murine IGF-II receptor and corresponding MS9II cells overexpressing the human IGF-II receptors. Our results show that IGF-II receptor overexpression increases the protein levels of APP. This is accompanied by an increase of ␤-site APP-cleaving enzyme 1 levels and an increase of ␤-and ␥-secretase enzyme activities, leading to enhanced A␤ production. At the cellular level, IGF-II receptor overexpression causes localization of APP in perinuclear tubular structures, an increase of lipid raft components, and increased lipid raft partitioning of APP. Finally, MS9II cells are more susceptible to staurosporine-induced cytotoxicity, which can be attenuated by ␤-secretase inhibitor. Together, these results highlight the potential contribution of IGF-II receptor to AD pathology not only by regulating expression/processing of APP but also by its role in cellular vulnerability. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss followed by the deterioration of higher cognitive functions. Although most cases of AD occur sporadically after the age of 60 years, a small proportion of cases correspond to the early-onset (Ͻ60 years) autosomal dominant form of the disease. To date, mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the presenilin 2 (PSEN2) gene on chromosome 1, have been identified as the cause of a large proportion of early-onset familial AD (1-3). Additionally, inheritance of the ε4 allele of the apolipoprotein E (APOE) gene on chromosome 19 increases the risk of late-onset and sporadic AD. The neuropathological features associated with AD include the presence of extracellular ␤-amyloid (A␤) peptidecontaining neuritic plaques, intracellular tau-positive neurofibrillary tangles, and the loss of synapses and neurons in defined brain regions. Several lines of in vivo evidence suggest that A␤ peptides initiate or contribute to the neuronal loss and development of AD pathology (2, 4). A␤ peptides are generated from APP, a type I transmembrane protein, which can be processed either by nonamyloidogenic ␣-secretase or amyloidogenic ␤-secretase pathways (5, 6). The ␣-secretase cleaves APP within the A␤ domain, yielding soluble APP␣ and a 10-kDa C-terminal fragment (CTF-␣), which then can be processed by ␥-secretase to generate A␤ 17-40 /A␤ 17-42 fragments. The ␤-secretase, on the other hand, cleaves APP to generate soluble APP␤ and an A␤-containing Cterminal fragment (CTF-␤), which is fu...

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Retromers in Alzheimer’s Disease

Cited by 28 publications

References 107 publications

Retromer: A Master Conductor of Endosome Sorting

Retromer: A Master Conductor of Endosome Sorting

Identification of novel transplantable GPCR recycling motif for drug discovery

Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

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