title: Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay.
abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy. sky569@libero.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.affiliation: Laboratory of Immunology, Institute of Experimental Endocrinology and Oncology, National Research Council (IEOS-CNR) c/o Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Procaccini
authors.affiliation: Molecular Medicine and Neuromuscular Laboratory, IRCCS Stella Maris, Pisa, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Meschini
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cianflone
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Carbone
authors.affiliation: Molecular Medicine and Neuromuscular Laboratory, IRCCS Stella Maris, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Doccini
authors.affiliation: Medical Pharmacology, Department of Neurology, CHRU University of Lille 2, Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Devos
authors.affiliation: Molecular Medicine and Neuromuscular Laboratory, IRCCS Stella Maris, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Nesti
authors.affiliation: Department of Neurobiology, Center of Biology-Pathology, CHRU University of Lille 2, Lille, France.
authors.forename: I
authors.initials: I
authors.lastname: Vuillaume
authors.affiliation: Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Filla
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: De Michele
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Salerno, Italy.|IRCCS Multimedica, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Molecular Medicine and Neuromuscular Laboratory, IRCCS Stella Maris, Pisa, Italy.
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D000328:Adult; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism*; D009128:Muscle Spasticity / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000150:complications / Q000151:congenital* / Q000235:genetics / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human
keywords: ARSACS; Mitochondrial dynamics; Mitochondrial metabolism; SACS; Sacsin