Characterizing upstream regulators of glucosylceramide metabolism for Parkinson's disease and Lewy Body Dementia

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Parkinson’s disease (PD)-associated dementia and Lewy Body Dementia (LBD) incidence is high among the aged population with 1% of those over 60 and 4% of those over 80. Mutations in the GBA gene represent one of the most common genetic risk factors for PD and LBD. GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) which converts glucosylceramide to ceramide and glucose, and PD patients with GBA mutations have earlier onset of disease and greater cognitive decline. Mutations in GBA leading to Parkinson’s lead to a reduction in GCase activity, and GCase activity is also significantly decreased in the substantia nigra and anterior cingulate cortex in sporadic PD and LBD cases, suggesting a critical role for GCase activity in the pathophysiology of PD and LBD. Importantly, glucosylceramide has been shown to promote aggregation of alpha-synuclein, leading to Lewy body formation. While there is no cure of PD or LBD, treatment is targeted primarily to improve symptoms, including L-DOPA and other dopamine agonists. However, as neuronal loss within the substantia nigra continues, the effectiveness of dopamine targeted therapies is greatly reduced. Therefore, identifying mechanisms to increase GBA activity may be an ideal method for therapeutic intervention for those patients harboring mutant GBA or reduced GCase activity. However, the upstream mechanisms regulating GBA activity remain unknown. We recently discovered that the S- adenosylmethionine (SAM) synthetase MAT2A may negatively regulate GBA activity thereby suggesting that inhibition of MAT2A may serve as a novel mechanism to upregulate GCase activity and provide a new treatment strategy for PD and LBD. Based on our preliminary data, we hypothesize that MAT2A negatively regulates GBA and therefore targeting MAT2A for inhibition may restore GBA activity in individuals with PD and LBD carrying mutations in GBA. We anticipate results in this study will define the molecular mechanism by which MAT2A controls GBA to influence glucosylceramide levels which are intimately linked to PD and LBD, assess whether reduced glucosylceramide in response to MAT2A inhibition will suppress alpha- synuclein aggregation and toxicity, as well as to identify new candidate genes involved in this pathway which could serve as additional potential therapeutic targets for PD and LBD. These studies will determine upstream regulatory mechanisms controlling glucosylceramide metabolism contributing to PD and LBD in both GBA-associated PD as well as patients who have altered GCase activity in the absence of GBA mutations. Furthermore, these studies will well serve as proof-of-principle for targeting MAT2A as a novel PD and LBD therapeutic strategy.