Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

被引：30

作者：

Compagnoni, Giacomo Monzio ^{[1
]}

Kleiner, Giulio ^{[2
]}

Bordoni, Andreina ^{[1
]}

Fortunato, Francesco ^{[1
]}

Ronchi, Dario ^{[1
]}

Salani, Sabrina ^{[1
]}

Guida, Marianna ^{[3
]}

Corti, Corrado ^{[3
]}

Pichler, Irene ^{[3
]}

Bergamini, Christian ^{[4
]}

Fato, Romana ^{[4
]}

Pellecchia, Maria Teresa ^{[5
]}

Vallelunga, Annamaria ^{[5
]}

Del Sorbo, Francesca ^{[6
]}

Elia, Antonio ^{[6
]}

Reale, Chiara ^{[7
]}

Garavaglia, Barbara ^{[7
]}

Mora, Gabriele ^{[8
]}

Albanese, Alberto ^{[9
]}

Cogiamanian, Filippo ^{[10
]}

Ardolino, Gianluca ^{[10
]}

Bresolin, Nereo ^{[1
]}

Corti, Stefania ^{[1
]}

Comi, Giacomo P. ^{[1
]}

Quinzii, Catarina M. ^{[2
]}

Di Fonzo, Alessio ^{[1
]}

机构：

[1] Univ Milan, Neurosci Sect, Dept Pathophysiol & Transplantat, Dino Ferrari Ctr,IRCCS Fdn Ca Granda Osped Maggio, Via Francesco Sforza 35, I-20122 Milan, Italy

[2] Columbia Univ, Dept Neurol, New York, NY 10032 USA

[3] Eurac Res, Inst Biomed, Via Galvani 31, I-39100 Bolzano, Italy

[4] Univ Bologna, Dept Pharm & Biotechnol FaBiT, Bologna, Italy

[5] Univ Salerno, Scuola Med Salernitana, Dept Med Surg & Dent, Neurosci Sect, Fisciano, SA, Italy

[6] Neurol Inst C Besta IRCCS Fdn, Neurol Unit 1, Milan, Italy

[7] IRCCS Fdn Ist Neurol Carlo Besta, Med Genet & Neurogenet Unit, Milan, Italy

[8] Ist Sci Milano, Dept Neurol Rehabil, ICS Maugeri, IRCCS, Milan, Italy

[9] Humanitas Res Hosp, Dept Neurol, Milan, Italy

[10] IRCCS Fdn Ca Granda Osped Maggiore Policlin, UO Neurofisiopatol, Milan, Italy

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2018年 / 1864卷 / 12期

关键词：

Multiple System Atrophy; Cellular models; Fibroblasts; Mitochondria; 3-NITROPROPIONIC ACID; COENZYME-Q10; LEVELS; ALPHA-SYNUCLEIN; MODEL; BIOMARKER; DISEASE; CELLS; MICE;

D O I：

10.1016/j.bbadis.2018.09.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondria! mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.

引用

页码：3588 / 3597

页数：10

共 41 条

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