Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:356

Article

Noelker, Carmen^1,2,3,4  Lu, Lixia^1,2,3  Hoellerhage, Matthias^4,8,9  Vulinovic, Franca⁶  Sturn, Annekathrin⁴  Roscher, Rene⁵  Hoeglinger, Guenter U.^4,8,9  Hirsch, Etienne C.^1,2,3  Oertel, Wolfgang H.⁴  Alvarez-Fischer, Daniel^1,2,3,6,7  Hartmann, Andreas^1,2,3 

[1] Univ Paris 06, INSERM, CR ICM, UMR S1127, F-75013 Paris, France

[2] Univ Paris 06, UMR S975, F-75013 Paris, France

[3] Grp Hosp Pitie Salpetriere, CR ICM, CNR5, UMR 7225, F-75013 Paris, France

[4] Univ Marburg, Fac Med, Dept Neurol, Marburg, Germany

[5] Actel Pharmaceut Ltd, CH-4123 Allschwil, Switzerland

[6] Med Univ Lubeck, Inst Neurogenet, D-23562 Lubeck, Germany

[7] Med Univ Lubeck, Dept Psychiat, D-23562 Lubeck, Germany

[8] Tech Univ Munich, Dept Neurol, D-80290 Munich, Germany

[9] German Ctr Neurodegenerat Dis DDIE, Dept Translat Neurodegenerat, Munich, Germany

关键词: Glucocerebrosidase;    Gaucher disease;    Parkinson's disease;    Dopamine cell death;    MPTP;    alpha-Syn;    Mitochondria;   

DOI  :  10.1016/j.jns.2015.06.030

来源: Elsevier

【 摘 要 】

Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57BI/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP+ (1-methyl-4-phenylpyridinium) or alpha-synuclein (alpha-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both a-Syn and MPP+ induced toxicity in vitro. However, only CBE-induced enhancement of MPP+ toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity. (C) 2015 Elsevier B.V. All rights reserved.

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