While the causes of Parkinson’s disease are not known, genetic and biochemical abnormalities of alpha-synuclein are directly implicated in the pathogenesis Parkinson’s disease and other alpha-synucleinopathies.
Transgenic mice expressing the A53T mutant human alpha-synuclein develop adult-onset disease with a progressive motor dysfunction leading to death. The affected mice exhibit many of the features of human alpha-synucleinopathies, including aberrant aggregation of alpha-synuclein and neurodegeneration in subcortical regions. Characterization of alpha-synucleinopathy in transgenic mice reveals signs of oxidative stress, including mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of Parkinson’s disease and other alpha-synucleinopathies, Project 2 will examine the pathological relationships between oxidative stress and alpha-synucleinopathies in the alpha-synuclein transgenic mice with Core B, Core C, and Core D.
First (Aim 1), they will determine whether the disease in the transgenic mice is associated with oxidative stress, particularly associated with mitochondrial abnormalities.
Second (Aims 2 and 3), they will test if oxidative stress act in concert with alpha-synuclein abnormalities exacerbate alpha-synuclein pathology and neurodegeneration.
Finally, they hypothesize that oxidative stress causes activation of c-Abl and c-Abl activation directly participates in the disease.
In collaboration with Project 1 they will show that alpha-synuclein pathology is associated with c-Abl activation in mice and in human Parkinson’s disease cases. They will show that lack of c-Abl function attenuates neurodegeneration in alpha-synuclein transgenic mice. Finally, they will show that c-Abl phosphorylates alpha-synuclein and such alpha-synuclein is preferentially found associated with the aggregates.
In addition, they will collaborate with Project 1 to determine if alpha-synuclein pathology leads to defects in parkin function and with Project 3 to determine link between mutant LRRK2 and alpha-synuclein pathology in vivo. These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches.