Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

Bustos, Victor; Pulina, Maria V.; Bispo, Ashley; Lam, Alison C; Flajolet, Marc; Gorelick, Fred S.; Greengard, Paul

doi:10.1073/pnas.1705240114

Cited by 70 publications

(69 citation statements)

References 33 publications

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“…Lack of phosphorylation on PS1 1 Ser367 impedes the fusion of autophagosome and lysosome in mouse brain. And then, this inhibition of autophagy reduced βCTF degradation leading to the accumulation of Aβ in the brain . These observations imply that PS1 could be a promising target for the treatment of AD through autophagy.…”

Section: Autophagy and Alzheimer's Diseasementioning

confidence: 81%

Autophagy in neurodegenerative diseases: pathogenesis and therapy

et al. 2017

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The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy-related pathways as therapeutic targets for the treatment of these diseases.

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Section: Autophagy and Alzheimer's Diseasementioning

confidence: 81%

Autophagy in neurodegenerative diseases: pathogenesis and therapy

et al. 2017

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“…Autophagy failure is commonly implicated in the pathological characteristics of AD 17 – 20 . Increasing evidences support that the function of PS1 affects autophagy process 21 – 25 . Serious impaired autophagy phenotypes such as accumulation of autophagic vacuoles and lysosomal dysfunction are observed in PS1-knockout mouse blastocysts, PS1-knockout mouse neurons, and mice brains with reduced levels of PS1 21 , 22 .…”

Section: Introductionmentioning

confidence: 99%

Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling

Chong

Tan

et al. 2018

Cell Death Dis

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Autophagy impairment is commonly implicated in the pathological characteristic of Alzheimer’s disease (AD). Presenilin 1 (PS1) expression in human brain gradually decreases with age and its mutations account for the most common cases of early-onset familial Alzheimer’s disease (FAD). The dominant autophagy phenotypes occur in PS1-knockout and PS1 mutant neurons; it is still unknown whether PS1 deficiency causes serious autophagy impairment in neural stem cells (NSCs). Herein, we generated the heterozygote and homozygote of PS1 knockout in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9-based gene editing and differentiated them into human NSCs. In these human PS1-deficient NSCs, reduced autophagosome formation and downregulated expression of autophagy–lysosome pathway (ALP)-related mRNAs, as well as proteins were observed. Mechanistically, ERK/CREB inhibition and GSK3β activation had key roles in reducing TFEB expression in PS1-knockout NSCs. Pharmacological inhibition of GSK3β upregulated the expression of TFEB and ALP-related proteins in PS1-knockout NSCs, whereas this effect could be blocked by CREB inhibition. These findings demonstrate that PS1 deficiency causes autophagy suppression in human NSCs via downregulating ERK/CREB signaling.

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“…Out of the mass spectrometry hits, found in two independent replicates, AnnexinA2 (human ANXA2) increased its affinity for LRRK2 upon α-syn PFF treatment. Intriguingly, ANXA2 is a phospholipid-binding protein that intervenes in phagocytic processes at multiple levels [56][57][58][59][60][61][62]. Specifically, it was reported that AnxA2 deficits are linked to a decreased endocytosis and particle internalization [56,63,64].…”

Section: Lrrk2 Interacts With Anxa2mentioning

confidence: 99%

Parkinson’s Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

Streubel-Gallasch

Giusti

Sandre

et al. 2020

Preprint

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BackgroundParkinson’s disease (PD) is a neurodegenerative, progressive disease without cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine rich repeat kinase 2 ( LRRK2 ) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. M utations in LRRK2 has been linked to impaired alpha-synuclein (α-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects α-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has recently received much attention and recent data indicate that astrocytes play a key role in α-syn mediated pathology. MethodsIn the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary α-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated α-syn for 24 hours and analyzed directly after the α-syn pulse or 6 days later. To elucidate the impact of LRRK2 on α-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy and proteomic approaches. ResultsOur results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar α-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of α-syn internalization in the Lrrk2 G2019S astrocytes is linked to Annexin A2 (AnxA2) loss-of-function. ConclusionTogether, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular α-syn aggregates through an AnxA2-dependent mechanism.

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Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

Cited by 70 publications

References 33 publications

Autophagy in neurodegenerative diseases: pathogenesis and therapy

Autophagy in neurodegenerative diseases: pathogenesis and therapy

Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling

Parkinson’s Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

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