Impact of Post-Translational Modifications on the Neurotoxicity of Alpha-Synuclein in Parkinson's Disease
Critical Challenges in PD: Translating Genetic Findings Into, 2007
The loss of neurons in the brains of Parkinson’s disease patients may be caused by harmful clusters or ‘aggregates’ of alpha-synuclein, an abundant protein in the central nervous system. Alpha-synuclein undergoes chemical modifications at different sites along the protein chain, and some of these changes are thought to stimulate the formation of toxic aggregates. The overall goal of this project is to determine which modifications of alpha-synuclein are involved in dopamine neuron death in Parkinson’s disease.
Alpha-Synuclein undergoes various chemical changes in neurons, including phosphorylation, nitration, and truncation. To test which of these plays a critical role in the death of dopamine neurons, we will prepare a series of genetically altered (or ‘mutant’) forms of alpha-synuclein in which each modification is either mimicked or prevented by an appropriate mutation in the protein’s amino-acid sequence. DNA encoding the mutant forms of alpha-synuclein will be introduced into cultured rat brain cells using viruses as genetic delivery agents. Cultures that produce different mutant forms of α-synuclein will be compared in terms of their numbers of dopamine neurons (determined by fluorescence microscopy) and their levels of alpha-synuclein aggregates (identified by their characteristic slow movement through a gel in an electric field).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our project is relevant to the treatment of Parkinson’s disease because it focuses on identifying new ways to prevent dopamine neuron killing by alpha-synuclein. Many of the chemical modifications explored in our study are carried out by specialized enzymes. If we prove that specific modifications are critical for the destruction of dopamine neurons by α-synuclein, then this discovery would justify the development of new therapies which inactivate the enzymes responsible for these harmful modifications.
Our study will enable us to compare genetically altered forms of alpha-synuclein (which have mutations that mimic or prevent chemical modifications) in terms of their ability to kill dopamine neurons and form aggregates. This information will indicate which chemical changes play the most important role in the destruction of dopamine neurons, and whether these modifications cause neuron death by favoring α-synuclein aggregation. Our findings will reveal whether dopamine neurons may be protected by preventing harmful chemical modifications of alpha-synuclein.
Professor at Purdue University
Location: West Lafayette, Indiana, United States