Autophagy-linked FYVE protein (Alfy) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)

Han, Huihui; Wei, Wanyi; Duan, Weisong; Guo, Yansu; Li, Yi; Wang, Jie; Bi, Yue; Li, Chunyan

doi:10.1007/s11626-014-9832-4

Cited by 21 publications

(20 citation statements)

References 39 publications

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“…Furthermore, autophagy-linked FYVE (Alfy) promotes the autophagic degradation of misfolded proteins involved in ALS. In this study, Alfy overexpression decreases the expression of mutant proteins through autophagy and reduces mutant protein toxicity ( Han et al, 2014 ). On the other hand, mutant SOD1 transgenic mice haploinsufficient for BECN1 show an unexpected increase in lifespan ( Nassif et al, 2014 ), showing a pathogenic and opposite role of BECN1 in the development of ALS.…”

Section: Autophagy In Neurodegenerationmentioning

confidence: 99%

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

Nah¹,

Yuan²,

Jung³

2015

Molecules and Cells

191

138

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Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis. Since the function of autophagy is particularly important in various stress conditions, perturbation of autophagy can lead to cellular dysfunction and diseases. Accumulation of abnormal protein aggregates, a common cause of neurodegenerative diseases, can be reduced through autophagic degradation. Recent studies have revealed defects in autophagy in most cases of neurodegenerative disorders. Moreover, deregulated excessive autophagy can also cause neurodegeneration. Thus, healthy activation of autophagy is essential for therapeutic approaches in neurodegenerative diseases and many autophagy-regulating compounds are under development for therapeutic purposes. This review describes the overall role of autophagy in neurodegeneration, focusing on various therapeutic strategies for modulating specific stages of autophagy and on the current status of drug development.

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Section: Autophagy In Neurodegenerationmentioning

confidence: 99%

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

Nah¹,

Yuan²,

Jung³

2015

Molecules and Cells

191

138

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“…Autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is an autophagy scaffold protein and was originally identified as a PI3P interacting protein localizing to autophagic membranes 21 . Upon autophagy-induction, ALFY translocates from the nucleus to the cytoplasm where it assists p62 in the autophagy-dependent degradation of ubiqutinated protein aggregates in neurodegenerative diseases 22 , 23 . ALFY interacts with ATG5 in a protein complex consisting of ATG12, ATG5 and ATG16L 24 , supporting the notion that ALFY is an autophagy scaffold protein 25 .…”

Section: Introductionmentioning

confidence: 99%

The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells

Schläfli

Isakson

Garattini

et al. 2017

Sci Rep

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Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of all-trans retinoic acid (ATRA) induce granulocytic differentiation of APL cells leading to cure rates of >80% if combined with conventional chemotherapy. Autophagy is a lysosomal degradation pathway for the removal of cytoplasmic content and recycling of macromolecules. ATRA induces autophagy in ATRA-sensitive AML and APL cells and autophagy inhibition attenuates ATRA-triggered differentiation. In this study, we aimed at identifying if the autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is involved in autophagic degradation of protein aggregates contributes to ATRA therapy-induced autophagy. We found that ALFY mRNA levels increase significantly during the course of ATRA-induced differentiation of APL and AML cell lines. Importantly ALFY depletion impairs ATRA-triggered granulocytic differentiation of these cells. In agreement with its function in aggrephagy, knockdown of ALFY results in reduced ATRA-induced proteolysis. Our data further suggest that PML-RARα is an autophagy substrate degraded with the help of ALFY. In summary, we present a crucial role for ALFY in retinoid triggered maturation of AML cells.

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“…Alfy, an autophagy adaptor protein, has been shown to facilitate autophagic degradation of protein aggregates and reduce the number of protein inclusions to prevent cytotoxicity [ 22 , 28 ]. We investigated whether WGA treatment altered Alfy expression in HeLa and SiHa cells.…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of Alfy decreased the number of protein inclusions and protected cells from expanded polyglutamine toxicity in an autophagy-dependent manner in a Drosophila eye model of Huntington disease [ 21 ]. Alfy also promoted the autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis suggesting it may be a useful target for the treatment of this disease [ 22 ]. Low levels of Alfy lead to increased ER stress and the aggregation of p62-positive polyubiquitinated proteins, which promoted autophagy in rheumatoid arthritis synovial fibroblasts [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Wheat germ agglutinin-induced paraptosis-like cell death and protective autophagy is mediated by autophagy-linked FYVE inhibition

et al. 2017

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Wheat germ agglutinin (WGA) is a lectin that specifically binds cell surface glycoproteins and disrupts nuclear pore complex function through its interaction with POM121. Our data indicate WGA induces paraptosis-like cell death without caspase activation. We observed the main features of paraptosis, including cytoplasmic vacuolation, endoplasmic reticulum dilation and increased ER stress, and the unfolded protein response in WGA-treated cervical carcinoma cells. Conversion of microtubule-associated protein I light chain 3 (LC3-I) into LC3-II and punctuate formation suggestive of autophagy were observed in WGA-treated cells. WGA-induced autophagy antagonized paraptosis in HeLa and CaSKi cells, which expressed autophagy-linked FYVE (Alfy) protein, but not in SiHa cells that did not express Alfy. Alfy knockdown in HeLa cells induced paraptosis-like cell death. These data indicate that WGA-induced cell death occurs through paraptosis and that autophagy may exert a protective effect. WGA treatment and Alfy inhibition could be an effective therapeutic strategy for apoptosis-resistant cervical cancer cells.

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Autophagy-linked FYVE protein (Alfy) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)

Cited by 21 publications

References 39 publications

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells

Wheat germ agglutinin-induced paraptosis-like cell death and protective autophagy is mediated by autophagy-linked FYVE inhibition

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