Mov Disord. 2015 Jun;30(7):989-91.
Plasma oligomeric alpha-synuclein is associated with glucocerebrosidase activity in Gaucher disease.
Nuzhnyi E1, Emelyanov A 1,2,3, Boukina T4, Usenko T 1,2, Yakimovskii A1, Zakharova E4, Pchelina S1,2,3
1First Pavlov’s State Medical University of Saint-Petersburg, St. Petersburg, Russia.
2Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
3St. Petersburg Academic University-Nanothecnology Research and Education Centre, RAS, St. Petersburg, Russia.
4Medical-genetics Scientific Center, Moscow, Russia.
The link between Parkinson’s disease (PD) and Gaucher disease (GD), the most common lysosomal storage disease associated with loss of glucocerebrosidase (GBA) activity, can be explained by abnormal accumulation of oligomeric alpha-synuclein (α-Syn) species resulting from mutations in the GBA gene. However, in GD, the relationship between GBA activity and α-Syn accumulation in biological fluids has not been investigated. We analyzed plasma oligomeric α-Syn levels, leucocyte GBA activity, and plasma chitotriosidase activity in 21 patients with GD. Negative correlation between plasma oligomeric α-Syn levels, and leucocyte GBA activity was observed in patients with GD (R2 = 0.487; P < 0.001). The decrease in GBA activity may influence α-Syn oligomerization, explaining the high risk of PD development in GD patients.
KEYWORDS: Gaucher disease; Parkinson’s disease; alpha-synuclein; glucocerebrosidase; oligomerization
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzhamer’s disease. Based on genetic, neuropathological and experimental data alpha-synuclein (SNCA), a synaptic protein with the propensity to aggregate, is considered now as the main key stone in PD pathogenesis. The disease specific mutations, that cause PD, have been discovered in last 15 years. The most recent discovery is the association of glucocerebrosidase (GBA) mutations with PD. Homozygous mutations in GBA cause the autosomal-recessive lysosomal storage disorder, Gaucher disease (GD). The genetic link between GD and PD is now widely accepted. Patients with PD are approximately six times more likely to carry GBA mutations than healthy control subjects. Heterozygous GBA mutations carriers as well as GD patient have strong risk for PD development. The mechanism by which GBA mutations are linked to PD remains unknown.
GBA is a lysosomal enzyme, which plays an important role in sphingolipid degradation, metabolizing glucocerebroside to glucose and ceramide. We and others drawn out a suggestion that lysosomal dysfunctions observed in GD could affect the levels of alpha-synuclein and facilitate its oligomerization in patients bearing mutations the GBA gene, as half of cellular alpha-synuclein is degraded via lysosomes. Our previous investigation has revealed an increased level of oligomeric (neurotoxic) alpha-synuclein, the main factor in PD pathogenesis, in plasma of GD patients vs. controls (1). Here we hypothesized that alpha-synuclein plasma levels in GD patients could be influenced by GBA activity.
The correlation between leucocyte GBA activity and plasma oligomeric alpha-synuclein in GD patients has been examined in the present study (2). As it turns out, our hypothesis was correct. Statistical analysis revealed a negative correlation between plasma oligomeric alpha-synuclein levels and the leucocyte GBA activity determined before treatment. Figure 1 shows the correlation between levels of plasma oligomeric alpha-synuclein and GBA activity in GD patients. Our data indicate that a reduction in GBA activity by pharmacological interventions or genetics factors may result in increased levels of alpha-synuclein aggregates.
Figure 1. Negative correlation between levels of plasma oligomeric alpha-synuclein and GBA activity in GD patients (R2=0,487, p<0,001). Patients who have not received enzyme replacement therapy (ERT) are marked with whites dots, who received ERT less than 5 years – with black dots.
The importance of this study is two-fold. This is the first study measuring GBA enzymatic activity as well as neurotoxic oligomeric alpha-synuclein specious in blood of GD patients baring mutations in the GBA gene in homozygous state. A decrease in GBA enzymatic activity and an increase in oligomeric alpha-synuclein levels could explain high risk of PD development in GBA mutation carriers.
Our study supports the notion that the insufficiency of GBA activity may influence alpha-synuclein oligomerization thus explaining the high risk of PD development in GBA mutation carriers. The negative correlation shown in this study supports the theory stating that accumulated GBA substrate (as the consequence of GBA insufficiency) may lead to stabilization of soluble oligomeric alpha-synuclein intermediates. It is also possible that GBA mutation lead lisosomal autophagy insufficiency and accumulation of alpha-synuclein leading to the formation of neurotoxic specious. Figure 2 illustrates both possible mechanisms.
On the other hand our data suject the possibility for therapeutic strategies augumenting GBA activity in treatment of GBA-associated PD. The most effectiveness is supposed now from noninhibitory chemical chaperones of GBA mutant enzyme, which could stabilize GBA and restored GBA activity. Such compounds may find an application in treatment of neuropathic forms of GD and GBA-associated PD and could open a new era of neuroprotective therapy.
Figure 2. Possible mechanisms of neudegeneration associated with mutation in the GBA gene. GBA mutations lead to decreased GBA enzymatic activity and GBA substrate accumulation. Glucocerebroside could directly stabilize neurotoxic alpha-synuclein specious. Otherwise, impaired lysosomal autoghagy could influence on alpha-synuclein degradation and lead to its oligomerization.
- Pchelina SN, Nuzhnyi EP, Emelyanov AK, Boukina TM, Usenko TS, Nikolaev MA, Salogub GN, Yakimovskii AF, Zakharova EY 2014 Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases. Neurosci Lett. 583:188-193
- Nuzhnyi E, Emelyanov A, Boukina T, Usenko T, Yakimovskii A, Zakharova E, Pchelina S 2016 Plasma oligomeric alpha-synuclein is associated with glucocerebrosidase activity in Gaucher disease. Mov Disord. 30(7):989-91
Acknowledgements: This study was supported by Russian foundation for basic research (№13-04-01510, №14-04-31665)
Sofya Pchelina, Dr Sci Head of Laboratory of Human Molecular genetics Petersburg Nuclear Physics Institute,
Leningrad area, Gatchina, Orlova Roscha, Russia, 188350
Head of Laboratory of Medical Genetics, First Pavlov’s State Medical University of Saint-Petersburg
L.Tolstogo str., 7-8, St.Petersburg, Russia, 197022