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Relationship between glucocerebrosidase (GCase) and neurologic diseases with Lewy bodies (2)

Mutated GCase or decreased levels of GCase cause a slowdown of alpha-synuclein degradation with the resulting formation of alpha-synuclein oligomers and fibrils (Cullen et al 2011; Yap et al 2011; Murphy et al 2014). Glucosylceramide stabilizes the alpha-synuclein oligomers (Mazzulli et al 2011), which are able to bind to the mutated glucocerebrosidase molecules and inhibit the enzymatic activity of glucocerebrosidase, further decreasing enzyme activity (Mazzulli et al 2011; Yap et al 2013a; 2015). These impaired lysosomes show impaired chaperone-mediated autophagy and autophagosome fusion. This results in an increased accumulation of alpha-synuclein in the cytoplasm, forming insoluble aggregates that ultimately form Lewy bodies. These aggregates block trafficking of GCase from the endoplasmic reticulum (ER) to the Golgi (Siebert et al 2014). Mutant GCase is retained in the endoplasmic reticulum, which causes ER stress and evokes the ER stress response (unfolded protein response) (Horowitz et al 2016). Saposin C can have a modulating effect on this by binding to Gcase, thus, maintaining its activity (Yap et al 2013b; Gruschus et al 2015).

Cullen V, Sardi SP, Ng J, et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol 2011;69(6):940-53.
Gruschus JM, Jiang Z, Yap TL, et al. Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C. Biochem Biophys Res Commun 2015;457(4):561-6.
Horowitz M, Elstein D, Zimran A, Goker-Alpan O. New directions in Gaucher disease. Hum Mutat 2016;37(11):1121-36.
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52.
Murphy KE, Gysbers AM, Abbott SK, et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. Brain 2014;137(Pt 3):834-48.
Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014;137(Pt 5):1304-22.
Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 2011;286(32):28080-8.
Yap TL, Gruschus JM, Velayati A, Sidransky E, Lee JC. Saposin C protects glucocerebrosidase against α-synuclein inhibition. Biochemistry 2013b;52(41):7161-3.
Yap TL, Jiang Z, Heinrich F, et al. Structural features of membrane-bound glucocerebrosidase and alpha-synuclein probed by neutron reflectometry and fluorescence spectroscopy. J Biol Chem 2015;290(2):744-54.
Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab 2013a;108(1):56-64.

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution [CC BY] License,