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Article ; Online: Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS.

Nethisinghe, Suran / Abeti, Rosella / Kesavan, Maheswaran / Wigley, W Christian / Giunti, Paola

International journal of molecular sciences

2021 Volume 22, Issue 21

Abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in ... ...

Abstract	Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the
MeSH term(s)	Cell Line ; Cells, Cultured ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Mitochondria/drug effects ; Mitochondria/metabolism ; Muscle Spasticity/drug therapy ; Muscle Spasticity/metabolism ; Novobiocin/analogs & derivatives ; Novobiocin/pharmacology ; Spinocerebellar Ataxias/congenital ; Spinocerebellar Ataxias/drug therapy ; Spinocerebellar Ataxias/metabolism ; Vimentin/metabolism
Chemical Substances	HSP90 Heat-Shock Proteins ; KU-32 compound ; VIM protein, human ; Vimentin ; Novobiocin (17EC19951N)
Language	English
Publishing date	2021-10-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222111722
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models.

Abeti, Rosella / Baccaro, Annalisa / Esteras, Noemi / Giunti, Paola

Frontiers in cellular neuroscience

2018 Volume 12, Page(s) 188

Abstract: Friedreich's Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, affecting dorsal root ganglia (DRG), cerebellar dentate nuclei and heart. It is caused by a GAA repeat expansion mutation within the frataxin gene ( ...

Abstract	Friedreich's Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, affecting dorsal root ganglia (DRG), cerebellar dentate nuclei and heart. It is caused by a GAA repeat expansion mutation within the frataxin gene (
Language	English
Publishing date	2018-07-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2018.00188
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Article: A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models.

Abeti, Rosella / Jasoliya, Mittal / Al-Mahdawi, Sahar / Pook, Mark / Gonzalez-Robles, Cristina / Hui, Chun Kiu / Cortopassi, Gino / Giunti, Paola

Frontiers in molecular biosciences

2022 Volume 9, Page(s) 830650

Abstract: Friedreich's ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic ... ...

Abstract	Friedreich's ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce
Language	English
Publishing date	2022-05-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.830650
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Article ; Online: Mitochondrial Ca(2+) in neurodegenerative disorders.

Abeti, Rosella / Abramov, Andrey Y

Pharmacological research

2015 Volume 99, Page(s) 377–381

Abstract: Functional mitochondria are vital to accomplish their key role in the cell, by maintaining the energy metabolism, buffering of the Ca(2+) signal and directing the cell death mechanism. Mitochondrial Ca(2+) can stimulate ATP production or trigger the ... ...

Abstract	Functional mitochondria are vital to accomplish their key role in the cell, by maintaining the energy metabolism, buffering of the Ca(2+) signal and directing the cell death mechanism. Mitochondrial Ca(2+) can stimulate ATP production or trigger the opening of mitochondrial permeability transition pore and activating the cell death cascade. Mitochondrial Ca(2+) uptake play a crucial role in neurons by buffering excessive Ca(2+) from the cytosol at the time of the transmission of the signal. Changes in the maintenance of mitochondrial Ca(2+) may trigger neuronal cell death. Abnormality in mitochondrial Ca(2+) handling has been detected in a range of neurodegenerative diseases, and emerging evidence from disease models suggests that mitochondrial Ca(2+) may play a role in disease pathogenesis. In this review, we assess how mitochondrial Ca(2+) imbalance may be a trigger in common neurodegenerative disease.
MeSH term(s)	Animals ; Calcium/metabolism ; Cell Death/physiology ; Humans ; Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-09
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2015.05.007
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Article ; Online: Hsp90 Inhibition

Suran Nethisinghe / Rosella Abeti / Maheswaran Kesavan / W. Christian Wigley / Paola Giunti

International Journal of Molecular Sciences, Vol 22, Iss 11722, p

A Promising Therapeutic Approach for ARSACS

2021 Volume 11722

Abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role ... ...

Abstract	Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.
Keywords	ARSACS ; ataxia ; vimentin ; KU-32 ; Hsp90 inhibition ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models

Rosella Abeti / Mittal Jasoliya / Sahar Al-Mahdawi / Mark Pook / Cristina Gonzalez-Robles / Chun Kiu Hui / Gino Cortopassi / Paola Giunti

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract: Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic ... ...

Abstract	Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.
Keywords	Friedreich’s Ataxia (FA) ; Frataxin (FXN) ; Dimethyl fumarate (DMF) ; Resveratrol (Resv) ; Mitochondrial membrane potential (ΔΨm) ; Reactive Oxygen species (ROS) ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology.

Abeti, Rosella / Brown, Alexander F / Maiolino, Marta / Patel, Sandip / Giunti, Paola

Frontiers in cellular neuroscience

2018 Volume 12, Page(s) 264

Abstract: Friedreich's Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small ... ...

Abstract	Friedreich's Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca
Language	English
Publishing date	2018-10-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2018.00264
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Article ; Online: Activation of PARP by oxidative stress induced by β-amyloid: implications for Alzheimer's disease.

Abeti, Rosella / Duchen, Michael R

Neurochemical research

2012 Volume 37, Issue 11, Page(s) 2589–2596

Abstract: Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterised by progressive cognitive impairment, dementia and atrophy of the central nervous system. The pathological hallmarks include the accumulation of the peptide β-amyloid ( ...

Abstract	Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterised by progressive cognitive impairment, dementia and atrophy of the central nervous system. The pathological hallmarks include the accumulation of the peptide β-amyloid (Aβ) which itself is toxic to neurons in culture. Recently, it has been discovered that Aβ activates the protein poly(ADP-ribosyl) polymerase-1 (PARP-1) specifically in astrocytes, leading indirectly to neuronal cell death. PARP-1 is a DNA repair enzyme, normally activated by single strand breaks associated with oxidative stress, which catalyses the formation of poly ADP-ribose polymers from nicotinamide adenine dinucleotide (NAD(+)). The pathological over activation of PARP-1 causes depletion of NAD(+) and leads to cell death. Here we review the relationship between AD and PARP-1, and explore the role played by astrocytes in neuronal death. AD has so far proven refractory to any effective treatment. Identification of these pathways represents a step towards a greater understanding of the pathophysiology of this devastating disease with the potential to explore novel therapeutic targets.
MeSH term(s)	Alzheimer Disease/enzymology ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Enzyme Activation ; Humans ; Oxidative Stress ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Amyloid beta-Peptides ; Reactive Oxygen Species ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2012-10-18
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-012-0895-x
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Article ; Online: Xeroderma pigmentosum: overview of pharmacology and novel therapeutic strategies for neurological symptoms.

Abeti, Rosella / Zeitlberger, Anna / Peelo, Colm / Fassihi, Hiva / Sarkany, Robert P E / Lehmann, Alan R / Giunti, Paola

British journal of pharmacology

2019 Volume 176, Issue 22, Page(s) 4293–4301

Abstract: Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP ... ...

Abstract	Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
MeSH term(s)	Humans ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Xeroderma Pigmentosum/complications ; Xeroderma Pigmentosum/drug therapy ; Xeroderma Pigmentosum/genetics ; Xeroderma Pigmentosum/metabolism
Language	English
Publishing date	2019-01-23
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14557
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Article ; Online: NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F

Strobbe, Daniela / Pecorari, Rosalba / Conte, Oriana / Minutolo, Antonella / Hendriks, Christine M M / Wiezorek, Stefan / Faccenda, Danilo / Abeti, Rosella / Montesano, Carla / Bolm, Carsten / Campanella, Michelangelo

British journal of pharmacology

2020 Volume 178, Issue 2, Page(s) 298–311

Abstract: Background and purpose: The mitochondrial F: Experimental approach: The chemical structure of the F: Key results: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement ...

Abstract	Background and purpose: The mitochondrial F Experimental approach: The chemical structure of the F Key results: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement of autophagy which impairs cell viability. NHS achieves such a function independently of the F Conclusion and implications: The novel sulfoximine analogue of BTB-06584, NHS, acts as a selective pharmacological inhibitor of the mitochondrial F
MeSH term(s)	Adenosine Triphosphate ; Cell Death ; Humans ; Hydrolysis ; Mitochondria/metabolism ; Proton-Translocating ATPases/metabolism
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; Proton-Translocating ATPases (EC 3.6.3.14)
Language	English
Publishing date	2020-12-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15279
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