ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

Mangieri, Leandra R.; Mader, Burton J.; Thomas, Cailin E.; Taylor, Charles A.; Luker, Austin M.; Tse, Tonia E.; Huisingh, Carrie; Shacka, John J.

doi:10.1371/journal.pone.0093257

Cited by 57 publications

(41 citation statements)

References 49 publications

(76 reference statements)

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“…Thus, endolysosome de-acidification by HIV-1 Tat might be caused by decreased vacuolar-ATPase. The HIV-1 Tat-induced decreases in vacuolar-ATPase and endolysosome de-acidification might then cause compensatory increases in cathepsin D and LAMP-1 (Mangieri et al, 2014), as we observed in these studies. Although SH-SY5Y cells over-expressing human AβPP are human Aβ processing neuronal cell cultures that are commonly used in AD-related studies, this non-physiological over-expression of AβPP may not fully reconstitute pathogenic cascades of HAND and may lead to supplementary pathogenic effects in addition to the accumulation of Aβ.…”

Section: Discussionsupporting

confidence: 58%

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

Soliman

Geiger

Chen

2016

J Neuroimmune Pharmacol

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The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer’s disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (Aβ) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase Aβ generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal Aβ generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced Aβ generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (AβPP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of Aβ as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of Aβ, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of Aβ. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent.

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Section: Discussionsupporting

confidence: 58%

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

Soliman

Geiger

Chen

2016

J Neuroimmune Pharmacol

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“…Other studies also observe the accumulation of endosomes and present evidence to indicate that it may be a consequence of impaired lysosomal proteolysis [102]. These data suggest that endosomes maybe one of the generation sites for Aβ as inhibiting the C-subunit of vacuolar-type H + -ATPase with bafilomycin, a macrolide antibiotic that inhibits vesicular acidification, leads to intracellular accumulation of both APP and CTFs within the cell [105–108]. This may be due to the processing of APP to CTFβ by BACE1, an aspartyl protease with an acid pH optimum, in an endosome where γ-secretase is also present and converts CTFβ to Aβ [25, 45].…”

Section: Cellular Maintenance and Aβ Regulationmentioning

confidence: 74%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

CAR

261

196

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Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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“…Several lines of recent evidence actually support the notion that the vATPase is not essential for autophagosome-lysosome fusion. [11][12][13] Enhanced Lc3 and Lamp1 colocalization following either knockdown or knockout of atp6v0ca, as well as of spns1, suggests that autophagic flux was inhibited primarily due to improper autolysosomal degradation rather than by a simple block in vesicular fusion. Nevertheless, Spns1 deficiency that also inhibits autophagic flux can be rescued by the loss or decrease of Atp6v0ca partially but significantly.…”

Section: Discussionmentioning

confidence: 99%

“…4 Moreover, cumulative lines of evidence suggest that autophagosome-lysosome fusion can still occur without v-ATPase-mediated acidification during endo-lysosomal biogenesis. [11][12][13] We hypothesized that the distinct phenotypes resulting from each single mutation, namely loss of acidification with atp6v0ca and loss of symport activity due to spns1, when combined result in a counteracting (i.e., suppressing) effect at the cellular and organismal levels. Therefore, because we could not rule out the possibility that the previous pharmacological approach may have had off-target effects, we concurrently knocked down and/or mutated both the spns1 and atp6v0ca genes in zebrafish embryos to validate their epistasis as well as biological endpoints such as autophagy, senescence and survival of the subject animals during early development.…”

Section: Introductionmentioning

confidence: 99%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H C -carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated. Using chemical, genetic and CRISPR/Cas9-mediated genome-editing approaches in zebrafish, we investigated and determined a mechanism that suppresses embryonic senescence as well as autolysosomal impairment mediated by Spns1 deficiency. Unexpectedly, we found that a concurrent disruption of the vacuolar-type H C -ATPase (v-ATPase) subunit gene, atp6v0ca (ATPase, H C transporting, lysosomal, V0 subunit ca) led to suppression of the senescence induced by the Spns1 defect, whereas the sole loss of Atp6v0ca led to senescent embryos similar to the single spns1 mutation. Moreover, we discovered that the combined stable defect seen in the presence of both the spns1 and atp6v0ca mutant genes still subsequently induced premature autophagosome-lysosome fusion marked by insufficient acidity, while extending developmental life span, compared with the solely mutated spns1 defect. Our data suggest that Spns1 and the v-ATPase orchestrate proper autolysosomal biogenesis with optimal acidification that is critically linked to developmental senescence and survival.

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ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

Cited by 57 publications

References 49 publications

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

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