Secretory carrier membrane protein 5 is an autophagy inhibitor that promotes the secretion of α-synuclein via exosome

Yang, Yi; Qin, Meiling; Bao, Puhua; Xu, Wangchao; Xu, Jin

doi:10.1371/journal.pone.0180892

Cited by 46 publications

(52 citation statements)

References 43 publications

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“…In vitro experiments using bafilomycin A (autophagy inhibitor, by preventing the fusion of autophagosome with lysosome) treatment resulted in impaired autophagic flux, as demonstrated by significant cellular accumulation of p62. We demonstrated that blocking the fusion of autophagosomes and lysosomes inhibits autophagic flux and promotes exosome secretion, as an alternative mechanism for the clearance of toxic proteins; our results are consistent with a recent study . Collectively, our results suggest that chronic alcohol administration affects lysosomes, thus disrupting autophagosome and lysosome fusion and exosome secretion.…”

Section: Discussionsupporting

confidence: 92%

“…We demonstrated that blocking the fusion of autophagosomes and lysosomes inhibits autophagic flux and promotes exosome secretion, as an alternative mechanism for the clearance of toxic proteins; our results are consistent with a recent study. (39) Collectively, our results suggest that chronic alcohol administration affects lysosomes, thus disrupting autophagosome and lysosome fusion and exosome secretion. Autophagy-exosome crosstalk is a complex and context-dependent process.…”

Section: Discussionmentioning

confidence: 73%

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Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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Cellular homeostais, that is normally maintained through autophagy, is disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized that increased exosome production in ALD may be linked to disruption of autophagic function. We found impaired autophagy both in ALD and alcoholic hepatitis (AH) mouse models and human livers with ALD as indicated by increased hepatic p62 and LC3‐II levels. Alcohol reduced autophagy flux in vivo in chloroquine‐treated mice as well as in vitro in hepatocytes and macrophages treated with bafilomycin A. Our results revealed that alcohol targets multiple steps in the autophagy pathway. Alcohol‐related decrease in mechanistic target of rapamycin (mTOR) and Ras homolog enriched in brain (Rheb), that initiate autophagy, correlated with increased Beclin1 and autophagy‐related protein 7 (Atg7), proteins involved in phagophore‐autophagosome formation, in ALD. We found that alcohol disrupted autophagy function at the lysosomal level through decreased lysosomal‐associated membrane protein 1 (LAMP1) and lysosomal‐associated membrane protein 2 (LAMP2) in livers with ALD. We identified that micro‐RNA 155 (miR‐155), that is increased by alcohol, targets mTOR, Rheb, LAMP1, and LAMP2 in the authophagy pathway. Consistent with this, miR‐155‐deficient mice were protected from alcohol‐induced disruption of autophagy and showed attenuated exosome production. Mechanistically, down‐regulation of LAMP1 or LAMP2 increased exosome release in hepatocytes and macrophages in the presence and absence of alcohol. These results suggested that the alcohol‐induced increase in exosome production was linked to disruption of autophagy and impaired autophagosome and lysosome function. Conclusion: Alcohol affects multiple genes in the autophagy pathway and impairs autophagic flux at the lysosome level in ALD. Inhibition of LAMP1 and LAMP2 promotes exosome release in ALD. We identified miR‐155 as a mediator of alcohol‐related regulation of autophagy and exosome production in hepatocytes and macrophages.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 73%

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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“…secretory carrier membrane protein 5, an autophagy flux inhibitor (Yang et al . ), was down‐regulated in the HIP (86.8%). Furthermore, we assayed the levels of other autophagy markers including LC3II (autophagosome formation), ATG5 (autophagosome elongation), and Beclin1 (autophagosome nucleation) by western blotting, all of which were clearly increased in the HIP and AMY (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Fang

Zeng

et al. 2018

Journal of Neurochemistry

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Menopause, a risk factor for brain dysfunction in women, is characterized by neuropsychological symptoms including depression and dementia, which are closely related to alterations in different brain regions after menopause. However, little is known about the variability in pathophysiologic changes associated with menopause in the brain. Here, we observed that menopause in rats induced by bilateral ovariectomy (OVX) showed depressive and dementia-related behaviors along with neuronal loss in the prefrontal cortex (PFC), hippocampus (HIP), hypothalamus (HYP), and amygdala (AMY) by Nissl staining. Meanwhile, by immunohistochemical staining, increased microglia in the HIP and AMY and increased astrocytes in the PFC, HYP, and AMY were shown. Using quantitative proteomics, we identified 146 differentially expressed proteins in the brains of OVX rats, for example, 20 in the PFC, 41 in the HIP, 17 in the HYP, and 79 in the AMY, and performed further detection by western blotting. A link between neuronal loss and apoptosis was suggested, as evidenced by increases in adenylate kinase 2 (AK2), B-cell lymphoma 2 associated X (Bax), cleaved caspase 3, and phosphorylated p53 and decreases in Huntingtin-interacting protein K, hexokinase, and phosphorylated B-cell lymphoma 2 (Bcl-2), and apoptosis might be triggered by endoplasmic reticulum stress (probed by increased glucose-regulated protein 78 (GRP78), cleaved caspase 12, phosphorylated protein kinase R (PKR)-like endoplasmic reticulum kinase, inositol-requiring enzyme-1 and activating transcription factor 6), and mitochondrial dysfunction (probed by increased cytochrome c and cleaved caspase 3 and decreased sideroflexin-1 (SFXN1) and NADH dehydrogenase (ubiquinone) 1 α subcomplex 11 (NDUFA11)). Activation of autophagy was also indicated by increased autophagy-related 7, γ-aminobutyric acid (GABA) receptor-associated protein-like 2, and oxysterol-binding protein-related protein 1 and confirmed by increased microtubule-associated protein light chain 3 (LC3II/I), autophagy-related 5, and Beclin1 in the HIP and AMY. In the AMY, which is important in emotion, higher GABA transporter 3 and lower vesicular glutamate transporter 1 levels indicated an imbalance between excitatory and inhibitory neurotransmission, and the increased calretinin and decreased calbindin levels suggested an adjustment of GABAergic transmission after OVX. In addition, cytoskeletal abnormalities including tau hyperphosphorylation, dysregulated Ca² signals, and glutamic synaptic impairments were observed in the brains of OVX rats. Collectively, our study showed the changes in different brain regions related to depression and dementia during menopause.

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“…In the top 10, 9 were found to be increased in HET versus WT. Four of these genes have previously been associated to α-synuclein pathology: TMEM230 [58], TMEM175 [41], B4GALNT1 [96] and SCAMP5 [100]. TMEM230 gene product is involved in the trafficking of synaptic vesicles and retromer components [49] and mutations in this gene have been linked to autosomal dominant PD [19].…”

Section: Age-dependent Neurodegeneration In the Dorsal Striatum But Nmentioning

confidence: 99%

“…Thus, the increase of B4GALNT1 and TMEM175 in 3M HET mice may indicate an attempt to counteract abnormal α-syn. SCAMP5 has been shown to modulate calcium-dependent exocytosis by interactng with SNAREs [108] and α-syn secretion via exomes in vitro [100]. The gene products of two DEGs, measured in blood, have been reported to be associated with PD: PSMC4 (26S proteasome AAA-ATPase subunit Rpt3, a component of the proteasome complex) [69] and COPZ1 (COPI coat complex subunit zeta 1, encoding a subunit of the cytoplasmic coatamer protein complex, which is involved in autophagy and intracellular protein trafficking) [79].…”

Section: Age-dependent Neurodegeneration In the Dorsal Striatum But Nmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

show abstract

Secretory carrier membrane protein 5 is an autophagy inhibitor that promotes the secretion of α-synuclein via exosome

Cited by 46 publications

References 43 publications

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

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