The Adaptive Immune System Is Not Necessary for α-synuclein Pathology Formation or Dopaminergic Neuron Loss After α-synuclein Pre-formed Fibril Injection
Esteban Luna1, Bin Zhang2, Virginia Lee2, Kelvin Luk2
1Neurology, Hospital of the University of Pennsylvania Neurology Department, 2University of Pennsylvania
Objective:
To understand the role of the adaptive immune (B & T cells) and innate immune systems (i.e. microglia) in Parkinson's Disease (PD) pathogenesis.
Background:
Intracellular aggregates of the protein α-synuclein (asyn) pathologically define PD, and mutations of asyn genetically link asyn to PD. Microglia, the chief immune cell of the CNS, and B & T cell activity have been implicated in PD neurodegeneration. How neuroinflammation mediated by these cells is involved in PD pathogenesis is a key knowledge gap.
Design/Methods:
I utilized 2 mouse lines that exhibit varying dysfunctional immune activity and C57BL/6 mice, which have intact adaptive and innate immune function. Rag2;IL2Rγ double knockout (RDKO) mice lack B & T cells and Non-obese Diabetic SCID Gamma (NSG) mice lack B & T cells and also contain innate immune dysregulation. I injected all 3 mouse strains intracerebrally with a misfolded form of recombinant asyn that can template native asyn in vivo replicating PD, termed pre-formed fibrils (PFFs). I then compared intracerebral neuroinflammatory gene expression profiles between the 3 mouse strains with a Nanostring microarray panel.
Results:
NSG mice developed 3-fold increased asyn protein inclusions and 2-fold worse neurodegeneration in the substantia nigra pars compacta by 6 months post injection compared to the control lines. There wasn't any difference between RDKO and C57BL/6. I found that the gene MPEG1 is downregulated 8-fold in NSG mice compared to the control lines using the Nanostring Neuroinflammation Gene Panel.
Conclusions:
These data show that the innate immune system mediates the potentiated phenotype in NSG mice after PFF injection independent of the adaptive immune system. Furthermore microglia may play role in PD neurodegeneration via the gene MPEG1. MPEG1 is a lysosomal protein found in microglia and involved in cytokine secretion. As a future direction, I aim to determine the role of MPEG1 in microglial cytokine secretion after PFF treatment.