Background Parkinson’s disease(PD)is characterised by degeneration of ventral midbrain dopaminergic(DA)neurons and abnormal deposition ofα-synuclein(α-syn)in neurons.Activation of the innate immune pathogen recogni...Background Parkinson’s disease(PD)is characterised by degeneration of ventral midbrain dopaminergic(DA)neurons and abnormal deposition ofα-synuclein(α-syn)in neurons.Activation of the innate immune pathogen recognition receptor toll-like receptor 2(TLR2)is associated with exacerbation ofα-syn pathology.TLR2 is increased on neurons in the PD brain,and its activation results in the accumulation and propagation ofα-syn through autophagy inhibition in neurons.In addition to the aggregation and propagation of pathologicalα-syn,dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD.However,the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address,given that TLR2 is a potential therapeutic target for PD.Methods Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons(including DA neurons)and astrocytes.Cells were treated with or without the TLR2 agonist Pam3CSK4,andα-syn pathology was seeded using pre-formed fibrils.Confocal imaging was used to assess lysosomal function andα-syn pathology in the different cell types,as well as DA neuron health and astrocyte activation.Results TLR2 activation acutely impaired the autophagy lysosomal pathway,and potentiatedα-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes,leading to degeneration and loss of DA neurons.The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulatedα-syn,and increases of A1 neurotoxic phenotypic proteins SerpinG1,complement C3,PSMB8 and GBP2.Moreover,the phenotypic changes in astrocytes correlated with a specific loss of DA neurons.Conclusions Taken together,these results support a role for astrocyte dysfunction inα-syn accumulation and DA neuronal loss following TLR2 activation in PD.展开更多
基金funded by a bequest from Francis Patrick Gill, the University of Sydney.F.W and L.H are funded by PhD scholarships from the University of Sydney.G.M.H.is a NHMRC Senior Leadership Fellow(#1176607).
文摘Background Parkinson’s disease(PD)is characterised by degeneration of ventral midbrain dopaminergic(DA)neurons and abnormal deposition ofα-synuclein(α-syn)in neurons.Activation of the innate immune pathogen recognition receptor toll-like receptor 2(TLR2)is associated with exacerbation ofα-syn pathology.TLR2 is increased on neurons in the PD brain,and its activation results in the accumulation and propagation ofα-syn through autophagy inhibition in neurons.In addition to the aggregation and propagation of pathologicalα-syn,dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD.However,the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address,given that TLR2 is a potential therapeutic target for PD.Methods Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons(including DA neurons)and astrocytes.Cells were treated with or without the TLR2 agonist Pam3CSK4,andα-syn pathology was seeded using pre-formed fibrils.Confocal imaging was used to assess lysosomal function andα-syn pathology in the different cell types,as well as DA neuron health and astrocyte activation.Results TLR2 activation acutely impaired the autophagy lysosomal pathway,and potentiatedα-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes,leading to degeneration and loss of DA neurons.The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulatedα-syn,and increases of A1 neurotoxic phenotypic proteins SerpinG1,complement C3,PSMB8 and GBP2.Moreover,the phenotypic changes in astrocytes correlated with a specific loss of DA neurons.Conclusions Taken together,these results support a role for astrocyte dysfunction inα-syn accumulation and DA neuronal loss following TLR2 activation in PD.
