Targeting alpha-synuclein through lipid interactions: potential new routes to disease modification in Parkinson’s

““We are learning a great deal about the disease mechanisms from the rarer forms of Parkinson’s caused by mutations. It is particularly encouraging is that this also sheds  some light on the common, sporadic disease form. In this paper, the greater understanding of underlying disease mechanisms has also led to the identification of a drug that might be tested in people with Parkinson’s.” Dr. Patrik Brundin

The build-up of abnormally folded alpha-synuclein is a known major culprit in Parkinson’s. Understanding what causes it to change shape and clump together is therefore a key step in stopping the disease. This work focuses on the build-up of GSLs as a significant trigger.

GSLs are handled within cells by the glucocerebrosidase (GCase) enzyme. Importantly, mutations in its gene, GBA1, are seen in Gaucher disease as well as a familial form of Parkinson’s. Gaucher disease is a condition caused by excessive GSL build-up in many different types of cells, not just neurons, with a broad range of symptoms.

To study the link between GBA1, GSLs and alpha-synuclein, these researchers used a variety of cell-free as well as stem cell methods. First, they chemically inhibited the action of the GCase enzyme mimicking Gaucher disease, and found that alpha-synuclein turned into its toxic form and reduced cell survival by 50%. Since GCase, which handles these lipids appropriately was inhibited, GSLs built up within cells. This then offered a window into the precise mechanism and steps of alpha-synuclein misfolding.

Not only did researchers succeed in understanding the role of a specific GSL (glucosylceramide – GluCer) in this process, but they also were able to reverse it by reducing GluCer with a drug used to treat type I Gaucher disease. This in turn reduced the amount of alpha-synuclein that misfolded into its toxic form. Importantly, the same results were seen in neurons without a GBA1 mutation, indicating that reducing GSLs as a therapeutic strategy could apply to more forms of Parkinson’s than just this rare genetic variant.

Phase 2 trials assessing the safety and efficacy of other agents targeting GCase are currently underway (see below). The case for Eliglustat (the drug used in the study) as a potential disease modifying agent in Parkinson’s merits consideration, but its safety and tolerability in people with Parkinson’s would first have to be firmly established.

Ambroxol trial

• CPT – Ambroxol, the facts
• Fox Trial Finder – Ambroxol

MOVES-PD trial

• http://news.genzyme.com/press-release/sanofi-initiates-phase-2-clinical-trial-evaluate-therapy-genetic-form-parkinsons-disea

MJFF – Living with Parkinson’s: GBA1 

 McEachern, K. A., Fung, J., Komarnitsky, S., Siegel, C. S., Chuang, W. L., Hutto, E., . . . Marshall, J. (2007). A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab, 91(3), 259-267.  https://www.ncbi.nlm.nih.gov/pubmed/17509920