Project Summary
This proposal aims to determine the contribution of T cells to pathology in an alpha-synuclein (a-syn)
based mouse model of Parkinson disease (PD). Our lab has pursued the idea that a-syn, an intracellular
protein abnormally aggregated in PD brains, is a trigger for the innate immune and adaptive immune system
activation associated with PD. Targeted overexpression of a-syn in the substantia nigra of mice driven by an
adeno-associated virus vector (AAV2-SYN) recapitulates the microgliosis, T cell infiltration, and slow
progressive cell death observed in human PD. Additionally, knocking out antigen processing machinery
(MHCII) reduces a-syn induced inflammation and neurodegeneration, suggesting a possible T cell mediated
disease mechanism. The proposed research attempts to build upon these findings, by investigating the
hypothesis that activation of T cells is required for mediating the dopaminergic neurotoxicity of alpha-synuclein
in vivo.
First, proposed experiments will determine whether alpha synuclein can lead to T cell activation in an
AAV2-SYN mouse model of PD. Changes in brain effector T cell populations will be measured through IHC
and flow cytometry in BL6 mice injected with AAV2-SYN or a control AAV2 vector (AAV2-GFP) at 2, 4, and 12
weeks post-injection. Next, experiments to determine the effect of T cells on myeloid activation in response to
a-syn will be conducted. Changes in activated myeloid populations will be measured in AAV2-SYN treated BL6
and mice lacking CD4 T cells (either by genetic KO or pharmacological treatment) by IHC and flow cytometry
2, 4, and 12 weeks post injection.
Lastly, the hypothesis that blocking T cells (either by genetic KO or pharmacological treatment) into the
CNS will reduce the neurodegeneration associated with a-syn overexpression will be tested. Both control BL6
mice and mice with a deficiency in CD4 T cells will be injected with AAV2-GFP and AAV2-SYN in the
substantia nigra. Dopaminergic neuron loss will be assessed at 6 months post-injection with unbiased
stereology. Collectively, the completion of these experiments will aid in the development of new therapeutics
targeting T cells that work to prevent neuroinflammation as a neuroprotective treatment for Parkinson disease.
The proposed training plan is sponsored by Dr. David Standaert and Dr. Ashley Harms. The overall
goal of the training plan is to provide the PI with a solid foundation for a successful career as a research
scientist studying neuroimmunology. Included in the training plan are experiences that help the PI: 1) gain
competence in a variety of techniques integrating neurobiology and immunology, 2) collaborate with other
scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively
integrate research with clinic, and 6) responsibly conduct research.