The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Martini‐Stoica, Heidi; Xu, Yin; Ballabio, Andrea; Zheng, Hui

doi:10.1016/j.tins.2016.02.002

Cited by 343 publications

(288 citation statements)

References 126 publications

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“…The particleladen phagophores mature into autophagosomes and fuse with late endosomes and lysosomes. All of these organelles show the capacity to store ARV nanoparticles (26,55). Here, we found that the number of autophagosomes was increased by URMC-099, and fusion of endosomes with autophagosomes led to the preferential localization of nanoformulated ARV particles in autophagosomes.…”

Section: Methodsmentioning

confidence: 65%

“…Nanoformulations of ATV and DTG were prepared by high-pressure homogenization (Avestin EmulsiFlex-C3; Avestin Inc.) (10, 65) (See the Supplemental Experimenof bioactive factors, and clearance vehicles for tissue metabolism and infectious materials cannot be overstated (28,55). Such seemingly complicated intracellular events can, paradoxically, sustain HIV-1 growth by sequestering cytoplasmic TFEB through HIV-1 Nef and inhibiting autophagy (25).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

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Section: Methodsmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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“…RF-EMF exposure significantly augments in the protein level of LC3B-II, which is a widely used marker for autophagosomes in the cerebral cortex, which reflect the relative amount of autophagosomes in cerebral cortical neurons. Eventually, the mature autophagosome fuses with a lysosome to form an autolysosome19.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is catabolic cellular degradation process responsible for degrading damaged organelles or unusual protein aggregates, which is activated in the presence of a variety of stimuli18. Suppression of autophagy may have a role in progression of cancers, neurodegenerative diseases, and infections, and is a common feature of aging1920. Therefore, autophagy plays an important role in maintaining cellular homeostasis and further functions protecting cells from various stressors21.…”

mentioning

confidence: 99%

Long-term exposure to 835 MHz RF-EMF induces hyperactivity, autophagy and demyelination in the cortical neurons of mice

Kim

Huh

et al. 2017

Sci Rep

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Radiofrequency electromagnetic field (RF-EMF) is used globally in conjunction with mobile communications. There are public concerns of the perceived deleterious biological consequences of RF-EMF exposure. This study assessed neuronal effects of RF-EMF on the cerebral cortex of the mouse brain as a proxy for cranial exposure during mobile phone use. C57BL/6 mice were exposed to 835 MHz RF-EMF at a specific absorption rate (SAR) of 4.0 W/kg for 5 hours/day during 12 weeks. The aim was to examine activation of autophagy pathway in the cerebral cortex, a brain region that is located relatively externally. Induction of autophagy genes and production of proteins including LC3B-II and Beclin1 were increased and accumulation of autolysosome was observed in neuronal cell bodies. However, proapoptotic factor Bax was down-regulted in the cerebral cortex. Importantly, we found that RF-EMF exposure led to myelin sheath damage and mice displayed hyperactivity-like behaviour. The data suggest that autophagy may act as a protective pathway for the neuronal cell bodies in the cerebral cortex during radiofrequency exposure. The observations that neuronal cell bodies remained structurally stable but demyelination was induced in cortical neurons following prolonged RF-EMF suggests a potential cause of neurological or neurobehavioural disorders.

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“…Transcription factor EB (TFEB), a member of the MiT/TFE subfamily of basic helix-loop-helix-leucine-zipper (bHLH-Zip) transcription factors, can enhance lysosomal biogenesis and autophagy [23-25] and ameliorate pathology of several human diseases, including neurodegenerative diseases [26], cancers [27-29], and lysosomal storage disorders [30]. Recent studies have demonstrated that activation of TFEB protects against cadmium-induced neurotoxicity through enhancing lysosomal biogenesis and autophagic flux [31], and the cytoprotective effect of moderate levels of Cu exposure is related to the activation of TFEB [32].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Induces Neuronal Apoptosis Through Suppressing Transcription Factor EB Phosphorylation at Ser467

Zheng

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: This study determined the role and mechanism of action of transcription factor EB (TFEB) in H₂O₂-induced neuronal apoptosis. Methods: SH-SY5Y cells were treated with Akt inhibitor/activator and different concentrations of H₂O₂. Cell apoptosis was detected by flow cytometric analysis. Akt and TFEB phosphorylation and PARP cleavage were determined by Western blotting. HEK293T cells were transfected with different truncated TFEB mutants and HA-Akt-WT; SH-SY5Y cells were transfected with Flag-vector, Flag-TFEB, Flag-TFEB-S467A or Flag-TFEB-S467D; and TFEB interaction with Akt was determined by co-immunoprecipitation and GST pull-down assays. Results: A low concentration of H₂O₂ induces TFEB phosphorylation at Ser467 and nuclear translocation, facilitating neuronal survival, whereas a high concentration of H₂O₂ promotes SH-SY5Y cell apoptosis via suppressing TFEB Ser467 phosphorylation and nuclear translocation. The TFEB-S467D mutant is more easily translocated into the nucleus than the non-phosphorylated TFEB-S467A mutant. Further, Akt physically binds to TFEB via its C-terminal tail interaction with the HLH domain of TFEB and phosphorylates TFEB at Ser467. Mutation of TFEB-Ser467 can prevent the phosphorylation of TFEB by Akt, preventing inhibition of oxidative stress-induced apoptosis. Conclusions: Oxidative stress induces neuronal apoptosis through suppressing TFEB phosphorylation at Ser467 by Akt, providing a novel therapeutic strategy for neurodegenerative diseases.

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The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Cited by 343 publications

References 126 publications

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Long-term exposure to 835 MHz RF-EMF induces hyperactivity, autophagy and demyelination in the cortical neurons of mice

Oxidative Stress Induces Neuronal Apoptosis Through Suppressing Transcription Factor EB Phosphorylation at Ser467

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