Scientific Results

Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay

Year: 2015

Authors: Criscuolo, C; Procaccini, C; Meschini, MC; Cianflone, A; Carbone, R; Doccini, S; Devos, D; Nesti, C; Vuillaume, I; Pellegrino, M; Filla, A; De Michele, G; Matarese, G; Santorelli, F

Autors Affiliation: Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, I-80131 Naples, Italy; Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Natl Res Council IEOS CNR, Inst Expt Endocrinol & Oncol,Immunol Lab, I-80131 Naples, Italy; IRCCS Stella Maris, Mol Med & Neuromuscular Lab, Pisa, Italy; Univ Lille 2, CHRU Lille, Dept Neurol, Med Pharmacol, Lille, France; Univ Lille 2, CHRU Lille, Ctr Biol Pathol, Dept Neurobiol, Lille, France; Univ Pisa, Translat Res & New Technol Med & Surg, Pisa, Italy; Univ Salerno, Dept Med & Surg, I-84100 Salerno, Italy; IRCCS Multimed, Milan, Italy

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.

Journal/Review: JOURNAL OF NEUROLOGY

Volume: 262 (12)      Pages from: 2755  to: 2763

More Information: This study was partially supported by grants from Fondazione Italiana Sclerosi Multipla (FISM) 2012/R/11, the European Union IDEAS Programme ERC-StG \”menTORingTregs\” (n.310496), FIRB-MERIT (n. RBNE08HWLZ_15), CNR-Program \”Medicina Personalizzata\” to GM, and Italian Ministry of Education, University, and Research (PRIN 2010-2011 20108WT59Y_007) to GDM. The sponsors had no role in study design, data collection and analysis, decision to publish or preparation of the paper.
DOI: 10.1007/s00415-015-7911-4

Citations: 21
data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2021-10-24
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