A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease

Chen, Dongfeng; Zhu, Cuiping; Wang, Xuenan; Feng, Xungang; Pang, Shuchao; Huang, Wenhui; Hawley, Robert G.; Yan, Bo

doi:10.1016/j.neulet.2013.01.044

Cited by 38 publications

(36 citation statements)

References 51 publications

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“…While it is very challenging to locate EndoA at the preautophagosome edge in vivo, highly curved membrane domains serve as docking sites for autophagic factors including Atg3, Atg14 and Atg1 (Fan et al, 2011;Nath et al, 2014;Ragusa et al, 2012 Macroautophagy mutants atg5 and atg7 display neurodegeneration and both genes are risk factors in PD (Chen et al, 2013a(Chen et al, , 2013bHara et al, 2006;Juhász et al, 2007;Komatsu et al, 2006). PD is often characterized by misfolded, dysfunctional proteins and synaptic dysfunction is recognized in PD models as well (Burke and O'Malley, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Macroautophagy mutants atg5 and atg7 display neurodegeneration and both genes are risk factors in PD (Chen et al, 2013a(Chen et al, , 2013bHara et al, 2006;Juhász et al, 2007;Komatsu et al, 2006). PD is often characterized by misfolded, dysfunctional proteins and synaptic dysfunction is recognized in PD models as well (Burke and O'Malley, 2013).…”

Section: Discussionmentioning

confidence: 99%

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A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals

Soukup

Kuenen

Vanhauwaert

et al. 2016

Neuron

218

285

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Manuscript 2Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turnover proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated. EndophilinA INTRODUCTIONNeurons can be metabolically very active, firing at rates of more than 100 Hz.Synaptic proteins and organelles are used and re-used multiple times and accumulate damage as a result of this stress. Furthermore, synapses are often located far away from the cell body and must therefore in part operate independently. This raises the question how synapses maintain protein quality. Given that neurodegeneration is thought to start with subtle synaptic defects before evolving into blunt neuronal death (Burke and O'Malley, 2013;, the mechanisms of synaptic protein homeostasis are likely relevant for the understanding of neurodegenerative disease.Macroautophagy is well-placed to mediate protein turnover, but how the needs of synapses are served by this process has not been well-studied. Cellular signals like stress and amino acid deprivation induce macroautophagy, where cytoplasm is engulfed by double membrane structures before fusion with degradative lysosomes (Mizushima et al., 2011).Autophagosomes have been visualized using fluorescent markers in yeast, Drosophila and mammalian cells and are often observed as Atg8/LC3 positive puncta (Kabeya et al., 2000;Scott et al., 2004). At the stage of initiation, Atg9-positive vesicles fuse into elongated preautophagosomal structures with growing edges (He et al., 2006). These edges are highly curved and harbor lipid packing defects. These edges serve as protein docking sites, attracting specific autophagic factors such as Atg3, Atg14/Barkor and Atg1 that insert into such zones, recognizing specific lipids (phosphatidylinositol-3-phosphate (PI(3)P)) and lipid packing defects (Fan et al., 2011;Nath et al., 2014;Ragusa et al., 2012). The recruitment of these factors then promotes the further steps of autophagosome formation; in particular the E2-like protein Atg3 itself recruits the autophagic marker LC3/Atg8 (Nath et al., 2014). However, how these highly curved edges are formed and maintained is very poorly understood.While autophagy has been mostly analyzed in the soma of cultured cells and yeast, autophagic markers have also been observed away from the soma at neuronal synapses 4 (Hernandez et al., 2012;Maday and Holzbaur, 2014;Williamson et al., 2010) and these markers were shown to be transported along axons (Maday and Holzbaur, 2014). However, how autophagosomes are formed at synapses an...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals

Soukup

Kuenen

Vanhauwaert

et al. 2016

Neuron

218

285

View full text Add to dashboard Cite

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“…Genetic variation in ATG5 has previously been linked to systemic lupus erythematosus (same SNP) [26], [27], asthma [19] and neurodegenerative disease [28], indicating the important role of ATG5 in human health and disease. However, the consequences of these genetic variants of ATG5 for the function of the protein are still unknown and warrant further investigation that should also include previously reported non-autophagic functions of ATG5 [29], [30].…”

Section: Discussionmentioning

confidence: 99%

Role of Genetic Variants of Autophagy Genes in Susceptibility for Non-Medullary Thyroid Cancer and Patients Outcome

et al. 2014

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Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04–3.23), P = 0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis.

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“…With regard to the UBL systems for example, mice with conditional deletion of Atg5 or Atg7 display similar Paneth cell defects 85 . Changes in the expression or properties of LC3 and GABARAP are found in Lewy body disease 86 , altered expression of ATG5 and ATG7 may contribute to sporadic Parkinson disease 87,88 , and an ATG7 mutation has been associated with earlier onset of Huntington disease 89 . Furthermore, ATG7 deficiency leads to liver disease 90,91 , and deletion or knockdown of Atg5 or Atg7 results in spontaneous tumor formation 92 , neurodegeneration 93,94 , and muscle myopathies 95,96 .…”

Section: Atg Ubl Proteins In Physiology and Diseasementioning

confidence: 99%

Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins

Klionsky

Schulman

2014

Nat Struct Mol Biol

248

224

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Autophagy complements the ubiquitin-proteasome system in mediating protein turnover. Whereas the proteasome degrades individual proteins modified with ubiquitin chains, autophagy degrades many proteins and organelles en masse. Macromolecules destined for autophagic degradation are “selected” through sequestration within a specialized double-membrane compartment termed the “phagophore”, the precursor to an “autophagosome”, and then hydrolyzed in a lysosome/vacuole-dependent manner. Notably, a pair of distinctive ubiquitin-like proteins (UBLs), Atg8 and Atg12, regulate degradation by autophagy in unique ways, by controlling autophagosome biogenesis and recruitment of specific cargos during selective autophagy. Here we review structural mechanisms underlying functions and conjugation of these UBLs that are specialized to provide interaction platforms linked to phagophore membranes.

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A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease

Cited by 38 publications

References 51 publications

A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals

A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals

Role of Genetic Variants of Autophagy Genes in Susceptibility for Non-Medullary Thyroid Cancer and Patients Outcome

Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins

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