Cx3cr1-deficiency exacerbates alpha-synuclein-A53T induced neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (alpha-SYN). Mutations of the gene that codes for alpha-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type alpha-SYN (alpha-SYNWT) or mutated alpha-SYN (alpha-SYNA53T) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1). We generated in vivo murine models overexpressing human alpha-SYNWT or alpha-SYNA53T in wild type (Cx3cr1(+/+)) or deficient (Cx3cr1(-/-)) mice for CX3CR1 using unilateral intracerebral injection of adeno-associated viral vectors. No changes in CX3CL1 levels were observed by immunofluorescence or analysis by qRT-PCR in this model. Interestingly, the expression alpha-SYNWT induced dopaminergic neuronal death to a similar degree in both genotypes. However, the expression of alpha-SYNA53T produced an exacerbated neurodegeneration, enhanced in the Cx3cr1(-/-) mice. This neurodegeneration was accompanied by an increase in neuroinflammation and microgliosis as well as the production of pro-inflammatory markers, which were exacerbated in Cx3cr1(-/-) mice overexpressing alpha-SYNA53T. Furthermore, we observed that in primary microglia CX3CR1 was a critical factor in the modulation of microglial dynamics in response to alpha-SYNWT or alpha-SYNA53T. Altogether, our study reveals that CX3CR1 plays an essential role in neuroinflammation induced by alpha-SYNA53T.