No abstract

Parkinson’s disease (PD) is characterized by intraneuronal inclusions of alpha-synuclein (α-Syn), neurodegeneration and a strong neuroinflammatory component. Studies have shown that genetic variants affecting quantity and quality of major histocompatibility complex II (MHCII) have implications in PD susceptibility and that PD patients have α-Syn specific T lymphocytes in circulation. The class II transactivator (CIITA) is the major regulator of MHCII expression and reduced CIITA expression has been shown to significantly increase α-Syn induced neurodegeneration and pathology in an α-Syn overexpression rat model combined with α-Syn pre-formed fibrils (PFF). In this study, we characterized immune profiles associated with the enhanced PD-like pathology observed in congenic rats with Ciita allelic variants causing lower CIITA levels compared to the background strain. Flow cytometry showed that rats with lower CIITA levels had an increased proportion of MHCII+ microglia and circulating myeloid cells, yet lower levels of MHCII on individual cells. Additionally, lower CIITA levels were associated to higher TNF levels in serum, trends of higher CD86 levels in circulating myeloid cells and a lower CD4/CD8 T lymphocyte ratio in blood. Taken together, these results indicate that CIITA regulates susceptibility to PD-like pathology through baseline immune populations and serum TNF levels.

Engrailed 1 (EN1) is a conserved transcription factor essential for programming, survival, and maintenance of midbrain dopaminergic neurons. En1-hemizygosity (En1+/-) leads to a spontaneous Parkinson's disease-like (PD-like) progressive nigrostriatal degeneration as well as motor impairment and depressive-like behavior in SwissOF1 (OF1-En1+/-) mice. This phenotype is absent in C57Bl/6j (C57-En1+/-) mice. Here we studied PD-like phenotypes and early transcriptome profiles in OF1 wild-type (WT) and OF1-En1+/- male mice and compare to that of C57 WT and C57-En1+/- male mice. To detect transcriptional changes prior to dopaminergic cell loss, we performed RNA-seq of 1-week old mice substantia nigra pars compacta (SNpc). Histology and stereology were used to assess dopaminergic nigrostriatal pathology in 4 and 16 weeks old mice. OF1-En1+/- mice showed an increase (+-61617;79%) in dopaminergic striatal axonal swellings from 4 to 16 weeks and a loss (+-61617;23%) of dopaminergic neurons in the SNpc at 16 weeks compared to OF1 WT. Axonal swellings were also present in C57-En1+/- mice but did not increase over time. 52 differentially expressed genes (DEGs) were observed between the C57-WT and the C57-En1+/- mice, while 198 DEGs were observed in the OF1 strain. Enrichment analysis revealed that the neuroprotective phenotype of C57-En1+/- mice was associated with an overexpression of oxidative phosphorylation-related genes compared to both C57 WT and to OF1- En1+/- mice. These results highlight the importance of considering genetic background in PD models and provide valuable insight on how expression of mitochondrial proteins before the onset of neurodegeneration is associated to vulnerability of nigrostriatal dopaminergic neurons.

No abstract

Parkinson's disease (PD) is a heterogeneous disorder characterized by intraneuronal inclusions of alpha-synuclein (α-Syn), a strong neuroinflammatory component and neurodegeneration. Human genetic association studies have shown that variants affecting quantity and quality of major histocompatibility complex II (MHCII) have implications in PD susceptibility and it was recently shown that PD patients have α-Syn specific T lymphocytes in circulation. The class II transactivator (Ciita) is the major regulator of MHCII expression and reduced Ciita expression has been shown to increase α-Syn induced neurodegeneration and pathology in vivo. Here we show, using flow cytometry in an α-Syn overexpression model combined with α-Syn pre-formed fibrils (PFF), that congenic rats with naturally occurring differences in Ciita expression have altered local and peripheral immune populations. Lower Ciita levels are associated with increased percentages of microglia and circulating myeloid cells being MHCII+ but with lower levels of MHCII on individual cells. Additionally, lower Ciita levels was associated to higher TNF levels in serum, trends of higher CD86 levels in circulating myeloid population and a lower CD4/CD8 T lymphocyte ratio. Taken together, these results indicate that Ciita regulates serum TNF levels and baseline immune populations which could mediate an increased susceptibility to PD-like pathology.