Investigating inflammatory responses in a novel rat model of G51D α-synuclein familial Parkinson’s disease

MRC Centre for Regenerative Medicine, The University of Edinburgh, UK; MRC Centre for Reproductive Health, The University of Edinburgh, UK

Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily manifesting as a movement disorder. It is characterised by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, intracellular protein aggregates majorly composed of α-synuclein.

Currently the mechanisms linking α-synuclein to dopaminergic neuron degeneration are not fully understood. Importantly, post-mortem analysis of PD patients has identified the presence of activated microglia and infiltrated T cells. Furthermore, PET imaging for the peripheral benzodiazapine receptor, expressed on cells of the macrophage lineage in the brain, revealed activated microglia present early in disease. These results suggest inflammatory processes may be important in disease initiation and progression. To further support the role of inflammation, animal models of PD employing toxin-induced ablation of dopaminergic cells have shown a reduction in degeneration, when microglial activation is inhibited. However, acute ablation of cells will result in exposure of the microglia to numerous damage-associated signals that could directly activate them. Furthermore, the acute ablation of neurons will remove the multiple inhibitory signals that keep microglia quiescent. These toxin models are not representative of the human condition where there is a slow accumulation of the toxic forms of α-synuclein and chronic neurodegeneration.

Our lab has CRISPR engineered a two nucleotide change in the endogenous rat α-synuclein gene to convert the glycine at position 51 to aspartic acid modelling a familial form of Parkinson’s disease. This model shows α-synuclein pathology and a down-regulation of transcripts important for dopaminergic cell function. This model aims to recapitulate a more pathologically relevant disease process where mutant α-synuclein can cause chronic pathology.

In this model, we are employing morphology analysis, gene expression analysis, and flow cytometry to probe microglia and other relevant immune populations to determine if we see changes to the inflammatory environment.

References

1. Lesage, S. et al. G51D α-synuclein mutation causes a novel Parkinsonian–pyramidal syndrome. Ann Neurol. 73, 459–471 (2013).
2. Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14, 38–48 (2013).
3. Gerhard, A. et al. In vivo imaging of microglial activation with [C-11](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412 (2006).
4. Du, Y. et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. 98, 14669–14674 (2001).

Funded by: MRC

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