Immune cells encounter with α-synuclein fuels neurodegeneration in Parkinson’s disease

Abstract

Abstract GBA1 mutations and increases of neuronal α-synulcein protein (α-syn) are the hallmark of Parkinson’s disease (PD). However, the mechanism, by which Gba1 mutation and or excess release of α-syn trigger neurodegeneration in PD is still wanted. Using Gba1 mouse model (D409V/null), we have observed increased level of α-syn and enhanced brain recruitment of inflammatory subsets of CD11chiCD11b+ CD86+DCs and CD3+CD4+ CD69+ T cells and their association with increased loss of CD45−CD11b− MAP2+ neurons and cognitive dysfunction. Performing adoptive transfer experiments, (e.g., WT cells → WT mice and Gba1 cells → Gba1 mice), augmented brain invasion of DCs and T cells, and neuronal cells destruction have been observed in Gba1 mouse. Searching the mechanism by which infiltrated immune cells could propagate brain inflammation in PD, DCs and CD4+T cells purified from WT and Gba1 mouse were used to perform their ex-vivo stimulation with α-syn and cytokines were measured. These data showed that α-syn treated Gba1 mouse immune cells cause marked increased generation of pro - inflammatory cytokines (e.g., IFNγ, TNFα, and IL6). Supernatant obtained from α-syn stimulated WT and Gba1 mouse DCs and CD4+T cells were used to perform in vitro stimulation of cortical neurons. These data showed that α-syn treated Gba1 mouse cells trigger increased neuronal death suggesting that increased brain penetration of immune cells and their encounter with α-syn propagate neurodegeneration in PD. Targeting DCs and / or CD4+ T cell function could be potential therapy to stop inflammation and neurodegeneration in PD.