Parkinson disease, the second most common
movement disorder, is a complex
neurodegenerative disorder hallmarked by the accumulation of
alpha-synuclein, a neural-specific small
protein associated with neuronal synapses. Mutations in the
glucocerebrosidase gene (GBA1), implicated in the rare, autosomal recessive lysosomal disorder
Gaucher disease, are the most common known genetic risk factor for
Parkinson disease. Insights into the inverse relationship between
glucocerebrosidase and
alpha-synuclein have led to new therapeutic approaches for the treatment of
Gaucher disease and GBA1-associated
Parkinson disease. Unlike the current drugs used to treat
Gaucher disease, which are highly expensive and do not cross the blood-brain-barrier, new small molecules
therapies, including competitive and non-competitive chaperones that enhance
glucocerebrosidase levels are being developed to overcome these limitations. Some of these include iminosugars,
ambroxol, other competitive
glucocerebrosidase inhibitors, and non-inhibitory chaperones or activators that do not compete for the active site. These drugs, which have been shown in different disease models to increase
glucocerebrosidase activity, could have potential as a
therapy for
Gaucher disease and GBA1- associated
Parkinson disease. Some have been demonstrated to reduce α-
synuclein levels in pre-clinical studies using cell-based or animal models of GBA1-associated
Parkinson disease, and may also have utility for
idiopathic Parkinson disease.