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Article ; Online: Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling.

Fedele, Anthony O / Proud, Christopher G

2020 Volume 40, Issue 4

Abstract: Autophagy is dependent upon lysosomes, which fuse with the autophagosome to complete the autophagic process and whose acidic interior permits the activity of their intraluminal degradative enzymes. Chloroquine (CQ) and bafilomycin A1 (BafA) each cause ... ...

Abstract	Autophagy is dependent upon lysosomes, which fuse with the autophagosome to complete the autophagic process and whose acidic interior permits the activity of their intraluminal degradative enzymes. Chloroquine (CQ) and bafilomycin A1 (BafA) each cause alkalinisation of the lumen and thus impair lysosomal function, although by distinct mechanisms. CQ diffuses into lysosomes and undergoes protonation, while BafA inhibits the ability of the vacuolar type H+-ATPase (v-ATPase) to transfer protons into the lysosome. In the present study, we examine the impact of CQ and BafA on the activity of mammalian target of rapamycin complex 1 (mTORC1), inhibition of which is an early step in promoting autophagy. We find each compound inhibits mTORC1 signalling, without affecting levels of protein components of the mTORC1 signalling pathway. Furthermore, these effects are not related to these agents' capacity to inhibit autophagy or the reduction in amino acid supply from lysosomal proteolysis. Instead, our data indicate that the reduction in mTORC1 signalling appears to be due to the accumulation of lysosomal storage material. However, there are differences in responses to these agents, for instance, in their abilities to up-regulate direct targets of transcription factor EB (TFEB), a substrate of mTORC1 that drives transcription of many lysosomal and autophagy-related genes. Nonetheless, our data imply that widely used agents that alkalinise intralysosomal pH are mimetics of acute lysosomal storage disorders (LSDs) and emphasise the importance of considering the result of CQ and BafA on mTORC1 signalling when interpreting the effects of these agents on cellular physiology.
MeSH term(s)	A549 Cells ; AMP-Activated Protein Kinases/metabolism ; Autophagosomes/drug effects ; Autophagosomes/metabolism ; Autophagy/drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Chloroquine/pharmacology ; HeLa Cells ; Humans ; Hydrogen-Ion Concentration/drug effects ; Lysosomal Storage Diseases/pathology ; Lysosomes/chemistry ; Lysosomes/drug effects ; Lysosomes/metabolism ; Macrolides/pharmacology ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Signal Transduction/drug effects ; Up-Regulation/drug effects ; Vacuolar Proton-Translocating ATPases/antagonists & inhibitors ; Vacuolar Proton-Translocating ATPases/metabolism
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Macrolides ; TFEB protein, human ; Chloroquine (886U3H6UFF) ; bafilomycin A1 (88899-55-2) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Vacuolar Proton-Translocating ATPases (EC 3.6.1.-)
Keywords	covid19
Language	English
Publishing date	2020-04-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20200905
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Article: Sanfilippo syndrome: causes, consequences, and treatments.

Fedele, Anthony O

The application of clinical genetics

2015 Volume 8, Page(s) 269–281

Abstract: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in ... ...

Abstract	Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway.
Language	English
Publishing date	2015-11-25
Publishing country	New Zealand
Document type	Journal Article ; Review
ISSN	1178-704X
ISSN	1178-704X
DOI	10.2147/TACG.S57672
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Article ; Online: Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation.

Hewson, Laura / Choo, Amanda / Webber, Dani L / Trim, Paul J / Snel, Marten F / Fedele, Anthony O / Hopwood, John J / Hemsley, Kim M / O'Keefe, Louise V

Journal of inherited metabolic disease

2024 Volume 47, Issue 2, Page(s) 340–354

Abstract: Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially ...

Abstract	Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep-wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.
MeSH term(s)	Animals ; Mucopolysaccharidosis III/diagnosis ; Drosophila melanogaster/metabolism ; Mutation ; Heparitin Sulfate ; Neuroglia
Chemical Substances	Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12712
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Article ; Online: SARS-CoV-2 produces a microRNA CoV2-miR-O8 in patients with COVID-19 infection.

Tucker, Elise J / Wong, Soon Wei / Marri, Shashikanth / Ali, Saira / Fedele, Anthony O / Michael, Michael Z / Rojas-Canales, Darling / Li, Jordan Y / Lim, Chuan Kok / Gleadle, Jonathan M

iScience

2023 Volume 27, Issue 1, Page(s) 108719

Abstract: Many viruses produce microRNAs (miRNAs), termed viral miRNAs (v-miRNAs), with the capacity to target host gene expression. Bioinformatic and cell culture studies suggest that SARS-CoV-2 can also generate v-miRNAs. This patient-based study defines the ... ...

Abstract	Many viruses produce microRNAs (miRNAs), termed viral miRNAs (v-miRNAs), with the capacity to target host gene expression. Bioinformatic and cell culture studies suggest that SARS-CoV-2 can also generate v-miRNAs. This patient-based study defines the SARS-CoV-2 encoded small RNAs present in nasopharyngeal swabs of patients with COVID-19 infection using small RNA-seq. A specific conserved sequence (CoV2-miR-O8) is defined that is not expressed in other coronaviruses but is preserved in all SARS-CoV-2 variants. CoV2-miR-O8 is highly represented in nasopharyngeal samples from patients with COVID-19 infection, is detected by RT-PCR assays in patients, has features consistent with Dicer and Drosha generation as well as interaction with Argonaute and targets specific human microRNAs.
Language	English
Publishing date	2023-12-13
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.108719
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Article ; Online: Cyclosporin A but not FK506 activates the integrated stress response in human cells.

Fedele, Anthony O / Carraro, Valérie / Xie, Jianling / Averous, Julien / Proud, Christopher G

The Journal of biological chemistry

2020 Volume 295, Issue 44, Page(s) 15134–15143

Abstract: Cyclosporin A (CsA) and tacrolimus (FK506) are valuable immunosuppressants for a range of clinical settings, including (but not limited to) organ transplantation and the treatment of autoimmune diseases. They function by inhibiting the activity of the ... ...

Abstract	Cyclosporin A (CsA) and tacrolimus (FK506) are valuable immunosuppressants for a range of clinical settings, including (but not limited to) organ transplantation and the treatment of autoimmune diseases. They function by inhibiting the activity of the Ca
MeSH term(s)	A549 Cells ; Activating Transcription Factor 4/metabolism ; Animals ; Cells, Cultured ; Cyclosporine/pharmacology ; HeLa Cells ; Humans ; Immunosuppressive Agents/pharmacology ; Mice ; Phosphorylation ; Stress, Physiological/drug effects ; Tacrolimus/pharmacology
Chemical Substances	ATF4 protein, human ; Immunosuppressive Agents ; Activating Transcription Factor 4 (145891-90-3) ; Cyclosporine (83HN0GTJ6D) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.014531
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Article ; Online: The gene for the lysosomal protein LAMP3 is a direct target of the transcription factor ATF4.

Burton, Thomas D / Fedele, Anthony O / Xie, Jianling / Sandeman, Lauren Y / Proud, Christopher G

The Journal of biological chemistry

2020 Volume 295, Issue 21, Page(s) 7418–7430

Abstract: Autophagy and lysosomal activities play a key role in the cell by initiating and carrying out the degradation of misfolded proteins. Transcription factor EB (TFEB) functions as a master controller of lysosomal biogenesis and function during lysosomal ... ...

Abstract	Autophagy and lysosomal activities play a key role in the cell by initiating and carrying out the degradation of misfolded proteins. Transcription factor EB (TFEB) functions as a master controller of lysosomal biogenesis and function during lysosomal stress, controlling most but, importantly, not all lysosomal genes. Here, we sought to better understand the regulation of lysosomal genes whose expression does not appear to be controlled by TFEB. Sixteen of these genes were screened for transactivation in response to diverse cellular insults. mRNA levels for lysosomal-associated membrane protein 3 (
MeSH term(s)	A549 Cells ; Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism ; Humans ; Lysosomal Membrane Proteins/biosynthesis ; Lysosomal Membrane Proteins/genetics ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Response Elements ; Transcription, Genetic ; Up-Regulation
Chemical Substances	ATF4 protein, human ; LAMP3 protein, human ; Lysosomal Membrane Proteins ; Neoplasm Proteins ; RNA, Messenger ; Activating Transcription Factor 4 (145891-90-3)
Language	English
Publishing date	2020-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.011864
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Article ; Online: Functional analysis of the HGSNAT gene in patients with mucopolysaccharidosis IIIC (Sanfilippo C Syndrome).

Fedele, Anthony O / Hopwood, John J

Human mutation

2010 Volume 31, Issue 7, Page(s) E1574–86

Abstract: Mucopolysaccharidosis (MPS) IIIC is an autosomal recessive lysosomal storage disorder caused by a deficiency in heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT). The characteristic feature is the deterioration of the central nervous ... ...

Abstract	Mucopolysaccharidosis (MPS) IIIC is an autosomal recessive lysosomal storage disorder caused by a deficiency in heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT). The characteristic feature is the deterioration of the central nervous system, but other symptoms may include coarse facies, developmental delay, macrocrania and motor retardation. HGSNAT is localised to the lysosomal membrane and catalyses a transmembrane acetylation in which the terminal glucosamine residue of heparan sulphate acquires an acetyl group, thus forming N-acetylglucosamine. 54 variants of the HGSNAT gene have been identified in MPS IIIC patients thus far, 22 of which are missense mutations. In this study, 20 of the latter were introduced into the cDNA of HGSNAT, and the resultant derivatives were exogenously expressed in cell culture. Transfection of 16 of these resulted in the synthesis of negligible HGSNAT protein and activity. The levels and function of the remaining 4 mutants, however, were similar to those of exogenously expressed wild-type HGSNAT. Interestingly, c.1209G>T (p.W403C), which is present in a variant classified in the former category, has only been sequenced in alleles also possessing c.1843G>A (p.A615T), which independently has a negligible effect on HGSNAT expression. This report suggests that these may function together to abolish HGSNAT activity.
MeSH term(s)	Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Cell Line ; Enzyme Assays ; Fluorescent Antibody Technique ; Humans ; Immunoblotting ; Mucopolysaccharidosis III/enzymology ; Mucopolysaccharidosis III/genetics ; Mucopolysaccharidosis III/pathology ; Mutagenesis, Site-Directed ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation ; Transfection
Chemical Substances	Mutant Proteins ; Acetyltransferases (EC 2.3.1.-) ; HGSNAT protein, human (EC 2.3.1.78)
Language	English
Publishing date	2010-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.21286
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Article: Lysosomal N-acetyltransferase interacts with ALIX and is detected in extracellular vesicles.

Fedele, Anthony O / Isenmann, Sandra / Kamei, Makoto / Snel, Marten F / Trim, Paul J / Proud, Christopher G / Hopwood, John J

Biochimica et biophysica acta. Molecular cell research

2018 Volume 1865, Issue 10, Page(s) 1451–1464

Abstract: Heparan acetyl CoA: α-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal multi-pass transmembrane protein whose deficiency may lead to an accumulation of heparan sulphate and the neurodegenerative lysosomal storage disorder mucopolysaccharidosis ( ... ...

Abstract	Heparan acetyl CoA: α-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal multi-pass transmembrane protein whose deficiency may lead to an accumulation of heparan sulphate and the neurodegenerative lysosomal storage disorder mucopolysaccharidosis (MPS) IIIC. In this study, HGSNAT activity was detected in extracellular vesicles isolated from both human urine and culture medium conditioned with HEK 293T cells. We also demonstrate that HGSNAT co-immunoprecipitates with antibodies to ALIX, which is associated with the endosomal sorting complexes required for transport (ESCRT) proteins, and is implicated in the targeting of proteins to intraluminal vesicles of multivesicular bodies, the origin of exosomes. Furthermore, mutation of a putative LYPX
Language	English
Publishing date	2018-07-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0167-4889 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2018.07.001
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Article ; Online: Sanfilippo syndrome

Fedele AO

The Application of Clinical Genetics, Vol 2015, Iss default, Pp 269-

causes, consequences, and treatments

2015 Volume 281

Abstract: Anthony O FedeleLysosomal Diseases Research Unit, South Australian Health and Medical ...

Abstract	Anthony O FedeleLysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA, AustraliaAbstract: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway.Keywords: lysosomal storage disease, Sanfilippo syndrome, mucopolysaccharidosis III
Keywords	Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	610 ; 150
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
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Article ; Online: Hypoxic induction of the regulator of G-protein signalling 4 gene is mediated by the hypoxia-inducible factor pathway.

Olechnowicz, Sam W Z / Fedele, Anthony O / Peet, Daniel J

PloS one

2012 Volume 7, Issue 9, Page(s) e44564

Abstract: The transcriptional response to hypoxia is largely dependent on the Hypoxia Inducible Factors (HIF-1 and HIF-2) in mammalian cells. Many target genes have been characterised for these heterodimeric transcription factors, yet there is evidence that the ... ...

Abstract	The transcriptional response to hypoxia is largely dependent on the Hypoxia Inducible Factors (HIF-1 and HIF-2) in mammalian cells. Many target genes have been characterised for these heterodimeric transcription factors, yet there is evidence that the full range of HIF-regulated genes has not yet been described. We constructed a TetON overexpression system in the rat pheochromocytoma PC-12 cell line to search for novel HIF and hypoxia responsive genes. The Rgs4 gene encodes the Regulator of G-Protein Signalling 4 (RGS4) protein, an inhibitor of signalling from G-protein coupled receptors, and dysregulation of Rgs4 is linked to disease states such as schizophrenia and cardiomyopathy. Rgs4 was found to be responsive to HIF-2α overexpression, hypoxic treatment, and hypoxia mimetic drugs in PC-12 cells. Similar responses were observed in human neuroblastoma cell lines SK-N-SH and SK-N-BE(2)C, but not in endothelial cells, where Rgs4 transcript is readily detected but does not respond to hypoxia. Furthermore, this regulation was found to be dependent on transcription, and occurs in a manner consistent with direct HIF transactivation of Rgs4 transcription. However, no HIF binding site was detectable within 32 kb of the human Rgs4 gene locus, leading to the possibility of regulation by long-distance genomic interactions. Further research into Rgs4 regulation by hypoxia and HIF may result in better understanding of disease states such as schizophrenia, and also shed light on the other roles of HIF yet to be discovered.
MeSH term(s)	Animals ; Base Sequence ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; DNA Primers ; Dactinomycin/administration & dosage ; Gene Expression Profiling ; Hypoxia/genetics ; Oligonucleotide Array Sequence Analysis ; PC12 Cells ; Polymerase Chain Reaction ; RGS Proteins/genetics ; RNA, Small Interfering ; Rats
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; DNA Primers ; RGS Proteins ; RNA, Small Interfering ; RGS4 protein (175335-35-0) ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; Dactinomycin (1CC1JFE158)
Language	English
Publishing date	2012-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0044564
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