Byline: Eric. Garcia, Ellen. Sidransky
The identification of genes increasing one's risk of developing common, complex disorders like Parkinson's disease (PD) can provide novel therapeutic opportunities. A prime example of this are the consequences of mutations in GBA1 , the gene responsible for the lysosomal storage disorder Gaucher disease (GD). GD is a multi-system disorder, primarily affecting tissues of the reticuloendothelial system. A subset of patients with GD also have neuronopathic manifestations (types 2 and 3 GD). In addition, there is an established association between GD and seemingly-unrelated movement disorders. First identified through clinical studies in patients and families with GD, mutations in GBA1 are the most significant genetic risk factor for PD and associated neurodegenerative disorders, including dementia with Lewy bodies and rapid eye movements sleep behavior disorders (Sidransky et al., 2009; Sidransky and Lopez, 2012; Honeycutt et al., 2019). This discovery has directed increased attention to lysosomal dysfunction in PD pathogenesis, rendering glucocerebrosidase (GCase), the enzyme encoded by GBA1 , an attractive target for therapeutic development, as recently reviewed by Chen et al. (2020).
The mechanisms underlying the association between mutations in GBA1 and parkinsonism are still not fully understood. Different hypotheses have been reviewed extensively elsewhere (Blandini et al., 2019; Do et al., 2019; Avenali et al., 2020). However, there appears to clearly be an inverse relationship between levels of glucocerebrosidase and the accumulation of alpha-synuclein. Furthermore, enzymatic studies of patients with PD reveal that even those without GBA1 mutations have reduced levels of glucocerebrosidase. Thus, therapies that increase glucocerebrosidase may have broad implications for the treatment of parkinsonism in general.
While 4-20% of patients with PD, depending on ethnicity, carry mutations in GBA1 , the penetrance is very low. Interestingly, patients with PD carrying GBA1 mutations have an earlier age-of-onset and faster disease progression of parkinsonian manifestations. However, a majority of GBA1 mutation carriers, even those with close family members with PD, do not develop parkinsonism (Sidransky and Lopez, 2012). Thus, other genetic and/or non-genetic modifiers may impact whether GBA1 mutation carriers eventually go on to develop PD. Identifying these secondary risk factors, or 'modifiers,' is particularly challenging, but these modifiers can have great significance and may potentially identify additional pathways or regulators that may serve as effective therapeutic targets (Davidson et al., 2018).
Enzyme replacement therapy, the first effective treatment for GD, reverses the hallmark symptoms of anemia, thrombocytopenia, and hepatosplenomegaly. Initially derived from placenta, several approved forms of the recombinant enzyme are now available. Though enzyme replacement therapy ameliorates the visceral phenotypes observed in patients, it does not effectively treat the neurological dysfunction in neuronopathic forms of GD due to its failure to cross the blood-brain barrier. Similarly, substrate reduction therapy, which reduces the synthesis of the stored sphingolipids, is ineffective in reversing neuronopathic symptoms (Bennett and Mohan, 2013). Given that GBA1 mutation carriers are at an increased risk of developing PD, novel therapeutics are needed to effectively treat the parkinsonian manifestations in patients with GBA1 - associated PD, and potentially, in other patients...