Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations
in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed
Parkinson disease has been found to be above that of the control population. This fact suggests that
mutations in the GBA gene can be involved in Parkison’s etiology. Analysis of large cohorts of patients
with Parkinson disease has shown that there are significantly more cases bearing GBA mutations
than those found among healthy individuals. Functional studies have proven an interaction between
α-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins
cause increases in α-synuclein levels, while an inhibition of GBA by α-synuclein has been also
demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition.
Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most
prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant
allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326
and L444) interact with Saposin C and, probably, also with α-synuclein. This could explain the antagonistic
role of these two proteins in relation to GBA.
Keywords: Gaucher disease, Parkinson disease, GBA mutations, E326K, L444P, saposin C, α-synuclein.
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