. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature. 2017 Mar 2;543(7643):108-112. Epub 2017 Feb 22 PubMed.


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  1. This very interesting paper from Gregory Grabowski and Jorg Kohl’s groups demonstrates, in a series of mouse studies, a link between glucocerebrosidase (GCase) deficiency and immune activation through the C5a/C5a receptor 1 (C5aR1) complement system. Their findings lead to the hypothesis that accumulation of glucosylcerabide (GC) results in complement activating IgG autoantibodies driving C5a generation and C5aR1 activation, which in turn results in additional GC accumulation and inflammatory system activation. The study included evidence of increases of serum C5a in patients with Gaucher disease. Finally, they demonstrated that C5aR1 antagonism, a potential therapeutic, led to reduced macrophage infiltration in peripheral tissues (lung, liver, spleen).

    Mutations in glucocerbrosidase are associated with both Gaucher and Parkinson’s disease, and both diseases have inflammatory processes linked to CNS involvement (Vitner EB et al., 2012; Allen Reish and Standaert, 2015). While this study did not examine the CNS, the results suggest end organ inflammation may be due to the interaction between the accumulation of GC and complement system activation. There is great interest in treating these disorders with GCase replacement (for example the MOVES-PD trial). This study suggests another approach, antagonism of C5aR1, which could be a novel therapeutic for these diseases.


    . Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis. 2015;5(1):1-19. PubMed.

    . Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease. Brain. 2012 Jun;135(Pt 6):1724-35. Epub 2012 May 7 PubMed.

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