The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb

Sun, Miao; Asghar, Suwaiba; Zhang, Huaye

doi:10.1016/j.nbd.2016.03.022

Cited by 25 publications

(44 citation statements)

References 60 publications

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“…Our recent studies found that there is a significant decrease in Par3 protein levels in the temporal cortex of AD patients (Sun et al, 2016). If abnormalities in Par3/aPKC regulated Ser498 phosphorylation are important for AD progression, one would predict to see a decrease in Ser498 phosphorylation in AD patients.…”

Section: Resultsmentioning

confidence: 99%

“…We found that Par3 regulates APP trafficking and intracellular Aβ generation in neurons (Sun et al, 2016). Here we found Par3 is also involved in the trafficking of BACE1; however, Par3 showed distinct effects on APP and BACE1.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have implicated Par3 in trafficking processes such as vesicle exocytosis (Ahmed and Macara, 2017; Balklava et al, 2007; Das et al, 2014; Lalli, 2009; Zuo et al, 2009). We recently showed that Par3 regulates APP trafficking through the endocytic adaptor Numb (Sun et al, 2016). Here we show an unexpected role for the polarity protein Par3 in regulating BACE1 endosome-to-TGN retrograde trafficking in hippocampal neurons.…”

Section: Introductionmentioning

confidence: 99%

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Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate limiting step in the generation of β-amyloid (Aβ) during Alzheimer’s disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in the endocytic compartments, where the acidic pH is optimal for its activity. However mechanisms that regulate the endosome-to-TGN retrieval of BACE1 under physiological conditions remain unclear. Here we show the Par polarity complex containing Par3 and aPKC facilitates BACE1 retrograde trafficking from the endosomes to the TGN. We further show that Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498. Finally, we found that Ser498 phosphorylation promotes the interaction between BACE1 and PACS1, which is necessary for the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in the AD pathogenic process. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1, and shed light on the mechanisms of AD pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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“…CMA is distinct from macroautophagy as CMA degradation pathway will accurately degrade certain proteins without engulf process and most of its degradation target proteins would be cytoplasm soluble proteins. This selective degradation pathway also contributes to maintenance of cellular homeostasis particularly under stress conditions together with other types of autophagy [44][45][46][47]. In the process of CMA mediated degradation, targeted protein will first be recognized and bind by a cytosolic chaperone, heat shock cognate protein of 70KD (hsc 70).…”

Section: Autophagy Malfunction In Admentioning

confidence: 99%

“…First of all, autophagy is believed to be another major Aβ clearance pathway besides those well-known Aβ degradation enzymes [56]. Autophagy facilitates the degradation and clearance of APP [57] as well as all APP cleavage products including Aβ [47,58], and APP-CTFs (amyloid precursor protein cleaved C-terminal fragment) [59]. In microglia, Aβ has also been found to be degraded by autophagy through the autophagy receptor optineurin [60].…”

Section: Autophagy Dysfunction and Ad-related Pathologymentioning

confidence: 99%

The role of autophagy in Alzheimer's disease

Li¹,

Sun²

2017

J Syst Integr Neurosci

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Autophagy is a key pathway to clear cellular abnormal protein aggregates, and is essential for protein homeostasis and neuronal health. Several studies have shown autophagy deficits may occur in early stage of Alzheimer's disease (AD). Regarding to Alzheimer's disease, autophagy itself plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its dysfunction may lead to the progress or aggravate of AD. By considering all published evidences, autophagy may be considered as a new target for developing AD targeted drugs. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD, and the potential therapeutic effects of autophagy modulators in AD.

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The physical approximation of APP and BACE‐1: A key event in alzheimer's disease pathogenesis

Sun

Roy

2017

Developmental Neurobiology

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Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid β (Aβ) in brains. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) by β-site secretase enzyme (BACE-1) and γ-secretase. Proteolytic processing of APP by BACE-1 is the rate-limiting step in Aβ production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway. Here, we highlight recent research on intracellular trafficking/sorting of APP and BACE-1, and discuss how dysregulation of these pathways might lead to enhanced convergence of APP and BACE-1, and subsequent β-cleavage of APP. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 340-347, 2018.

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The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb

Cited by 25 publications

References 60 publications

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

The role of autophagy in Alzheimer's disease

The physical approximation of APP and BACE‐1: A key event in alzheimer's disease pathogenesis

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