Source: Northwestern University
Summary: Researchers have discovered how a gene mutation results in a buildup of a toxic compound known to cause Parkinson’s disease symptoms, defining for the first time the mechanism underlying that aspect of the disease.
In Parkinson’s, a protein called alpha-synuclein is converted to insoluble, toxic clusters in the central nervous system, but the exact mechanism of conversion was unknown until now. One of the strongest risk factors for developing these clusters is a mutation in the gene GBA1, which normally degrades a lipid called glucosylceramide. Patients with one mutation in the gene suffer an increased level of glucosylceramide and have been shown to have a 5-fold increased risk for Parkinson’s; patients with two mutant forms of the gene, one inherited from each parent, can develop Gaucher’s disease (a lysosomal storage disorder). Researchers from the Northwestern University used this genetic connection to elucidate the mechanism of GBA1-influenced Parkinson’s disease. The study findings were published in the journal Neuron.
Using stem cell models of neurons, the research team used a pharmacological inhibitor to increase levels of glucosylceramide without a mutated GBA1 gene. Even without the mutation, this resulted in a dramatic build-up of toxic α-synuclein in neurons. This suggested that the critical factor in converting alpha-synuclein from its normal form to its pathogenic form was not necessarily the presence of the mutated GBA1 protein, but more importantly the decreased activity and glucosylceramide accumulation. These discoveries suggest that future therapies targeting this pathway might utilize drugs originally intended for treating Gaucher’s disease. While the pharmaceutical industry has been interested in the use of those lipid-reducing agents for some time, this study defines the molecular process behind those efforts and demonstrates how it might work.
Asst. Prof. Joseph Mazzulli said, “Our ultimate goal is to reduce alpha-synuclein levels in patients, however measuring the levels of α-synuclein from the central nervous system of a living patient is complicated”, “It’s far easier to measure the effects of therapeutics that alter glucosylceramide in patients, since the lipid can be directly measured from easily accessible fluids, such as blood or cerebral spinal fluid.”
More Information: Friederike Zunke et al, “Reversible Conformational Conversion of α-synuclein into Toxic Assemblies by Glucosylceramide”, Neuron (2017). DOI: https://doi.org/10.1016/j.neuron.2017.12.012