Study Rationale:
Evidence suggests that the protein alpha-synuclein can cause the death of neurons in the brains of people with Parkinson’s disease (PD) by forming clusters (or aggregates) on the surface of small spherical structures inside the cell called vesicles. Chemical modifications (post-translational modifications) have been identified in models of PD, as well as in the brains of people with PD. Nothing is known about the effects of these modifications on the ability of alpha-synuclein to form aggregates on vesicle surfaces.
Hypothesis:
This study addresses the hypothesis that certain post-translational modifications of alpha-synuclein enhance the protein’s ability to form aggregates on the surface of vesicles, resulting in neuronal death.
Study Design:
Alpha-synuclein variants with individual or multiple post-translational modifications will be generated by linking together protein fragments prepared using a combination of bacterial production and chemical synthesis. Each modified full-length alpha-synuclein variant will be compared to unmodified alpha-synuclein in terms of its ability to form aggregates on the surface of vesicles and to cause the breakage of vesicle membranes, a consequence of alpha-synuclein aggregation on vesicle surfaces. Post-translational modifications that enhance aggregate formation will be further tested for their effects on alpha-synuclein aggregation and toxicity in cellular models established in our laboratories.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our study will enable us to identify post-translational modifications that enhance alpha-synuclein’s ability to form aggregates on vesicle surfaces. These insights will advance our understanding of molecular processes involved in neuron death and set the stage for developing treatments to prevent alpha-synuclein post-translational modifications in the brains of people with PD.
Next Steps for Development:
The next steps toward clinical application of our findings will be to (i) investigate whether post-translational modifications identified in this project enhance alpha-synuclein’s aggregation and toxicity in models of PD; and (ii) screen for compounds that prevent harmful post-translational modifications as potential therapies to slow neuron death.