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Article ; Online: Autophagy Function and Benefits of Autophagy Induction in Models of Spinocerebellar Ataxia Type 3.

Watchon, Maxinne / Luu, Luan / Plenderleith, Stuart K / Yuan, Kristy C / Laird, Angela S

2023 Volume 12, Issue 6

Abstract: Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the : Methods: Here, we investigated whether the autophagy ... ...

Abstract	Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the Methods: Here, we investigated whether the autophagy protein quality control pathway, which is important in the process of protein aggregate removal, is impaired in a cell culture and zebrafish model of SCA3. Results: We found that SH-SY5Y cells expressing human ataxin-3 containing polyglutamine expansion exhibited aberrant levels of autophagy substrates, including increased p62 and decreased LC3II (following bafilomycin treatment), compared to the controls. Similarly, transgenic SCA3 zebrafish showed signs of autophagy impairment at early disease stages (larval), as well as p62 accumulation at advanced age stages (18 months old). We then examined whether treating with compounds known to induce autophagy activity, would aid removal of human ataxin-3 84Q and improve the swimming of the SCA3 zebrafish larvae. We found that treatment with loperamide, trehalose, rapamycin, and MG132 each improved the swimming of the SCA3 zebrafish compared to the vehicle-treated controls. Conclusion: We propose that signs of autophagy impairment occur in the SH-SY5Y model of SCA3 and SCA3 zebrafish at larval and advanced age stages. Treatment of the larval SCA3 zebrafish with various compounds with autophagy induction capacity was able to produce the improved swimming of the zebrafish, suggesting the potential benefit of autophagy-inducing compounds for the treatment of SCA3.
MeSH term(s)	Animals ; Humans ; Infant ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/metabolism ; Ataxin-3/genetics ; Zebrafish/metabolism ; Neurodegenerative Diseases ; Neuroblastoma ; Autophagy/physiology
Chemical Substances	Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2023-03-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12060893
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Article ; Online: Spermidine treatment: induction of autophagy but also apoptosis?

Watchon, Maxinne / Wright, Amanda L / Ahel, Holly I / Robinson, Katherine J / Plenderleith, Stuart K / Kuriakose, Andrea / Yuan, Kristy C / Laird, Angela S

Molecular brain

2024 Volume 17, Issue 1, Page(s) 15

Abstract: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a ... ...

Abstract	Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.
MeSH term(s)	Humans ; Animals ; Mice ; Neurodegenerative Diseases ; Spermidine/pharmacology ; Spermidine/therapeutic use ; Zebrafish ; Apoptosis ; Autophagy ; Disease Models, Animal ; Machado-Joseph Disease
Chemical Substances	Spermidine (U87FK77H25)
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2436057-0
ISSN	1756-6606 ; 1756-6606
ISSN (online)	1756-6606
ISSN	1756-6606
DOI	10.1186/s13041-024-01085-7
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Article: Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias.

Robinson, Katherine J / Watchon, Maxinne / Laird, Angela S

Frontiers in neuroscience

2020 Volume 14, Page(s) 707

Abstract: The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that share convergent disease features. A common symptom of these diseases is development of ataxia, involving impaired balance and motor coordination, usually ... ...

Abstract	The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that share convergent disease features. A common symptom of these diseases is development of ataxia, involving impaired balance and motor coordination, usually stemming from cerebellar dysfunction and neurodegeneration. For most spinocerebellar ataxias, pathology can be attributed to an underlying gene mutation and the impaired function of the encoded protein through loss or gain-of-function effects. Strikingly, despite vast heterogeneity in the structure and function of disease-causing genes across the SCAs and the cellular processes affected, the downstream effects have considerable overlap, including alterations in cerebellar circuitry. Interestingly, aberrant function and degeneration of Purkinje cells, the major output neuronal population present within the cerebellum, precedes abnormalities in other neuronal populations within many SCAs, suggesting that Purkinje cells have increased vulnerability to cellular perturbations. Factors that are known to contribute to perturbed Purkinje cell function in spinocerebellar ataxias include altered gene expression resulting in altered expression or functionality of proteins and channels that modulate membrane potential, downstream impairments in intracellular calcium homeostasis and changes in glutamatergic input received from synapsing climbing or parallel fibers. This review will explore this enhanced vulnerability and the aberrant cerebellar circuitry linked with it in many forms of SCA. It is critical to understand why Purkinje cells are vulnerable to such insults and what overlapping pathogenic mechanisms are occurring across multiple SCAs, despite different underlying genetic mutations. Enhanced understanding of disease mechanisms will facilitate the development of treatments to prevent or slow progression of the underlying neurodegenerative processes, cerebellar atrophy and ataxic symptoms.
Language	English
Publishing date	2020-07-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2020.00707
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Article ; Online: A Novel Calpain Inhibitor Compound Has Protective Effects on a Zebrafish Model of Spinocerebellar Ataxia Type 3.

Robinson, Katherine J / Yuan, Kristy / Plenderleith, Stuart K / Watchon, Maxinne / Laird, Angela S

Cells

2021 Volume 10, Issue 10

Abstract: Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the ... ...

Abstract	Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the human
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Ataxin-3/drug effects ; Disease Models, Animal ; Glycoproteins/metabolism ; Neurodegenerative Diseases/drug therapy ; Zebrafish
Chemical Substances	Antineoplastic Agents ; Glycoproteins ; calpain inhibitors ; Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2021-09-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10102592
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Article ; Online: Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.

Watchon, Maxinne / Robinson, Katherine J / Luu, Luan / An, Yousun / Yuan, Kristy C / Plenderleith, Stuart K / Cheng, Flora / Don, Emily K / Nicholson, Garth A / Lee, Albert / Laird, Angela S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 38, Issue 2, Page(s) e23429

Abstract: Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein ... ...

Abstract	Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent-insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB-treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in vitro and in vivo. While our results suggested that this activity may involve activity of a PKA/AMPK-dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.
MeSH term(s)	Humans ; Animals ; Butyric Acid/pharmacology ; Ataxin-3/genetics ; Machado-Joseph Disease/drug therapy ; Machado-Joseph Disease/genetics ; Zebrafish ; AMP-Activated Protein Kinases ; Neurodegenerative Diseases ; Protein Aggregates ; Proteomics ; Neuroblastoma ; Autophagy ; Animals, Genetically Modified ; Cyclic AMP-Dependent Protein Kinases
Chemical Substances	Butyric Acid (107-92-6) ; Ataxin-3 (EC 3.4.19.12) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Protein Aggregates ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202300963RR
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 296: Show issues

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Article ; Online: Flow cytometry allows rapid detection of protein aggregates in cellular and zebrafish models of spinocerebellar ataxia 3.

Robinson, Katherine J / Tym, Madelaine C / Hogan, Alison / Watchon, Maxinne / Yuan, Kristy C / Plenderleith, Stuart K / Don, Emily K / Laird, Angela S

Disease models & mechanisms

2021 Volume 14, Issue 10

Abstract: Spinocerebellar ataxia 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disease caused by inheritance of a CAG repeat expansion within the ATXN3 gene, resulting in polyglutamine (polyQ) repeat expansion within the ataxin-3 protein. ... ...

Abstract	Spinocerebellar ataxia 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disease caused by inheritance of a CAG repeat expansion within the ATXN3 gene, resulting in polyglutamine (polyQ) repeat expansion within the ataxin-3 protein. In this study, we have identified protein aggregates in both neuronal-like (SHSY5Y) cells and transgenic zebrafish expressing human ataxin-3 with expanded polyQ. We have adapted a previously reported flow cytometry methodology named flow cytometric analysis of inclusions and trafficking, allowing rapid quantification of detergent insoluble forms of ataxin-3 fused to a GFP in SHSY5Y cells and cells dissociated from the zebrafish larvae. Flow cytometric analysis revealed an increased number of detergent-insoluble ataxin-3 particles per nuclei in cells and in zebrafish expressing polyQ-expanded ataxin-3 compared to those expressing wild-type human ataxin-3. Treatment with compounds known to modulate autophagic activity altered the number of detergent-insoluble ataxin-3 particles in cells and zebrafish expressing mutant human ataxin-3. We conclude that flow cytometry can be harnessed to rapidly count ataxin-3 aggregates, both in vitro and in vivo, and can be used to compare potential therapies targeting protein aggregates. This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Ataxin-3/metabolism ; Autophagy/drug effects ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Disease Models, Animal ; Flow Cytometry ; Green Fluorescent Proteins/metabolism ; Humans ; Machado-Joseph Disease/pathology ; Neurons/metabolism ; Peptides ; Protein Aggregates ; Solubility ; Zebrafish/physiology
Chemical Substances	Peptides ; Protein Aggregates ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9) ; polyglutamine (26700-71-0) ; Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2021-10-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049023
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Article ; Online: Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo.

Watchon, Maxinne / Luu, Luan / Robinson, Katherine J / Yuan, Kristy C / De Luca, Alana / Suddull, Hannah J / Tym, Madelaine C / Guillemin, Gilles J / Cole, Nicholas J / Nicholson, Garth A / Chung, Roger S / Lee, Albert / Laird, Angela S

Molecular brain

2021 Volume 14, Issue 1, Page(s) 128

Abstract: Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate ( ... ...

Abstract	Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.
MeSH term(s)	Acetylation ; Animals ; Animals, Genetically Modified ; Ataxin-3/antagonists & inhibitors ; Ataxin-3/genetics ; Ataxin-3/metabolism ; Autophagy/drug effects ; Carbazoles/pharmacology ; Carbazoles/therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Synergism ; Genes, Reporter ; HEK293 Cells ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Histones/metabolism ; Humans ; Machado-Joseph Disease/drug therapy ; Peptides/genetics ; Protein Processing, Post-Translational ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Resveratrol/pharmacology ; Resveratrol/therapeutic use ; Signal Transduction ; Sirtuin 1/physiology ; Sirtuins/drug effects ; Sirtuins/physiology ; Swimming ; Trinucleotide Repeat Expansion ; Valproic Acid/pharmacology ; Valproic Acid/therapeutic use ; Zebrafish ; Zebrafish Proteins/antagonists & inhibitors ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ; Carbazoles ; Histone Deacetylase Inhibitors ; Histones ; Peptides ; Recombinant Fusion Proteins ; Repressor Proteins ; Zebrafish Proteins ; polyglutamine (26700-71-0) ; Valproic Acid (614OI1Z5WI) ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12) ; SIRT1 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-) ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2021-08-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2436057-0
ISSN	1756-6606 ; 1756-6606
ISSN (online)	1756-6606
ISSN	1756-6606
DOI	10.1186/s13041-021-00839-x
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Article ; Online: Pathophysiological interplay between

Pereira Sena, Priscila / Weber, Jonasz J / Watchon, Maxinne / Robinson, Katherine J / Wassouf, Zinah / Hauser, Stefan / Helm, Jacob / Abeditashi, Mahkameh / Schmidt, Jana / Hübener-Schmid, Jeannette / Schöls, Ludger / Laird, Angela S / Riess, Olaf / Schmidt, Thorsten

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 47

Abstract: ... ...

Abstract	Aberrant
MeSH term(s)	Animals ; Ataxin-3/genetics ; Ataxin-3/metabolism ; Disease Models, Animal ; HEK293 Cells ; Humans ; Machado-Joseph Disease/metabolism ; Machado-Joseph Disease/pathology ; N-Acetylglucosaminyltransferases/metabolism ; Peptides ; Proteasome Endopeptidase Complex ; Zebrafish/metabolism
Chemical Substances	Peptides ; polyglutamine (26700-71-0) ; N-Acetylglucosaminyltransferases (EC 2.4.1.-) ; O-GlcNAc transferase (EC 2.4.1.-) ; Ataxin-3 (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2021-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2025810118
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Zs.A 1148: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Conserved anti-inflammatory effects and sensing of butyrate in zebrafish.

Cholan, Pradeep Manuneedhi / Han, Alvin / Woodie, Brad R / Watchon, Maxinne / Kurz, Angela Rm / Laird, Angela S / Britton, Warwick J / Ye, Lihua / Holmes, Zachary C / McCann, Jessica R / David, Lawrence A / Rawls, John F / Oehlers, Stefan H

Gut microbes

2020 Volume 12, Issue 1, Page(s) 1–11

Abstract: Short-chain fatty acids (SCFAs) are produced by microbial fermentation of dietary fiber in the gut. Butyrate is a particularly important SCFA with anti-inflammatory properties and is generally present at lower levels in inflammatory diseases associated ... ...

Abstract	Short-chain fatty acids (SCFAs) are produced by microbial fermentation of dietary fiber in the gut. Butyrate is a particularly important SCFA with anti-inflammatory properties and is generally present at lower levels in inflammatory diseases associated with gut microbiota dysbiosis in mammals. We aimed to determine if SCFAs are produced by the zebrafish microbiome and if SCFAs exert conserved effects on zebrafish immunity as an example of the non-mammalian vertebrate immune system. We demonstrate that bacterial communities from adult zebrafish intestines synthesize all three main SCFA
MeSH term(s)	Acetates/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Butyrates/metabolism ; Butyrates/pharmacology ; Dietary Fiber/metabolism ; Dysbiosis/microbiology ; Gastrointestinal Microbiome/physiology ; Macrophages/drug effects ; Macrophages/immunology ; Male ; Neutrophils/drug effects ; Neutrophils/immunology ; Propionates/pharmacology ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Wounds and Injuries/immunology ; Zebrafish/embryology ; Zebrafish/immunology
Chemical Substances	Acetates ; Anti-Inflammatory Agents ; Butyrates ; Dietary Fiber ; Propionates ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2020-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2575755-6
ISSN	1949-0984 ; 1949-0984
ISSN (online)	1949-0984
ISSN	1949-0984
DOI	10.1080/19490976.2020.1824563
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Article: Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in

Frontiers in molecular neuroscience

2021 Volume 14, Page(s) 627740

Abstract: The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical ... ...

Abstract	The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g., SOD1), regulation of RNA homeostasis (e.g., TDP-43 and FUS), and protein degradation through the ubiquitin-proteasome system (e.g., ubiquilin-2 and cyclin F) and autophagy (TBK1 and sequestosome-1/p62). It is likely that the various initial triggers of disease (either genetic, environmental and/or gene-environment interaction) must converge upon a common set of molecular pathways that underlie ALS pathogenesis. Given the complexity, it is not surprising that a catalog of molecular pathways and proteostasis dysfunctions have been linked to ALS. One of the challenges in ALS research is determining, at the early stage of discovery, whether a new gene mutation is indeed disease-specific, and if it is linked to signaling pathways that trigger neuronal cell death. We have established a proof-of-concept proteogenomic workflow to assess new gene mutations, using CCNF (cyclin F) as an example, in cell culture models to screen whether potential gene candidates fit the criteria of activating apoptosis. This can provide an informative and time-efficient output that can be extended further for validation in a variety of
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2021.627740
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