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Chronic pharmacological glucocerebrosidase inhibition induces α-synuclein aggregation, microglial and complement activation and synaptic protein changes in mice.

著者 Rocha EM , Smith GA , Park E , Cao H , Graham AR , Brown E , McLean JR , Hayes MA , Beagan J , Izen SC , Perez-Torres E , Hallett PJ , Isacson O
Antioxid Redox Signal.2015 Jun 21 ; ():.
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Loss-of-function mutations in GBA1 are a genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy Bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme results in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. PD-patients who harbor a loss-of-function GBA1 mutation usually develop more severe symptoms, are often diagnosed earlier and are associated with increased α-synuclein accumulation than non-GBA1 mutation carrying PD-patients. Deficits in autophagy and lysosomal degradation proteins likely contribute to pathological accumulation of α-synuclein in PD and animal models of the disease. Therefore, we hypothesized that pharmacological inhibition of glucocerebrosidase promotes α-synucleinopathy by disrupting lysosomal degradation pathways and cause histopathological changes reminiscent of the α-synucleinopathies.
PMID: 26094487 [PubMed - as supplied by publisher]
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