Development and biochemical characterization of a mouse model of Parkinson's disease bearing defective glucocerebrosidase activity

Neurobiology of Disease

Fabio Blandini¹  Liudmila Mus²  Silvia Cerri²  Christina Ghezzi²  Claudio Giuliano²  Francesca Siani² 

[1] Corresponding author at: Laboratory of Functional Neurochemistry, IRCCS Mondino Foundation, via Mondino 2, 27100 Pavia, Italy.;Laboratory of Functional Neurochemistry, IRCCS Mondino Foundation, Pavia, Italy;

关键词: Glucocerebrosidase;    α-Synuclein;    CBE;    MPTP;    Parkinson's disease;    Mouse model;   

DOI  :  

来源: DOAJ

【 摘 要 】

GBA1 gene encodes for the lysosomal membrane protein glucocerebrosidase (GCase). GBA1 heterozygous mutations profoundly impair GCase activity and are currently recognized as an important risk factor for the development of Parkinson's disease (PD). Deficits in lysosomal degradation pathways may contribute to pathological α-synuclein accumulation, thereby favoring dopaminergic neuron degeneration and associated microglial activation. However, the precise mechanisms by which GCase deficiency may influence PD onset and progression remain unclear. In this work we used conduritol-β-epoxide (CBE), a potent inhibitor of GCase, to induce a partial, systemic defect of GCase activity comparable to that associated with heterozygous GBA1 mutations, in mice. Chronic (28 days) administration of CBE (50 mg/kg, i.p.) was combined with administration of a classic PD-like inducing neurotoxin, such as MPTP (30 mg/kg, i.p. for 5 days). The aim was to investigate whether a pre-existing GCase defect may influence the effects of MPTP in terms of nigrostriatal damage, microglia activation and α-synuclein accumulation. Pre-treatment with CBE had tendency to enhance MPTP-induced neurodegeneration in striatum and caused significant increase of total α-synuclein expression in substantia nigra. Microglia was remarkably activated by CBE alone, without further increases when combined with MPTP. Overall, we propose this model as an additional tool to study pathophysiological processes of PD in the presence of GCase defects.

【 授权许可】

Unknown