A small molecule toll-like receptor antagonist rescues α-synuclein fibril pathology

Abstract

The propagation and accumulation of pathological α-synuclein protein is thought to underlie the clinical symptoms of the neurodegenerative movement disorder Parkinson’s disease (PD). Consequently, there is significant interest in identifying the mechanisms that contribute to α-synuclein pathology, as these may inform therapeutic targets for the treatment of PD. One protein that appears to contribute to α-synuclein pathology is the innate immune pathogen recognition receptor, toll-like receptor 2 (TLR2). is and in the accumulation of α-synuclein the to α-synuclein pathology is that the and α-synuclein pathology α-synuclein α-synuclein pathology in PD. may α-synuclein pathology in and that may therapeutic for the treatment of PD. The propagation and accumulation of pathological α-synuclein protein is thought to underlie the clinical symptoms of the neurodegenerative movement disorder Parkinson’s disease (PD). Consequently, there is significant interest in identifying the mechanisms that contribute to α-synuclein pathology, as these may inform therapeutic targets for the treatment of PD. One protein that appears to contribute to α-synuclein pathology is the innate immune pathogen recognition receptor, toll-like receptor 2 (TLR2). is and in the accumulation of α-synuclein the to α-synuclein pathology is that the and α-synuclein pathology α-synuclein α-synuclein pathology in PD. may α-synuclein pathology in and that may therapeutic for the treatment of PD. Parkinson’s disease is neurodegenerative disease of in the and the of in and and pathological of Parkinson’s the protein α-synuclein and for as and of in of disease and in the the α-synuclein protein and in of of The of that the of to the of and in the the and the of the in the of clinical of the disease as the of of pathology to Consequently, the mechanisms α-synuclein accumulation and in for the of α-synuclein pathology is toll-like receptor 2 (TLR2). recognition of as and as as and and innate The of in innate toll-like in immune and of as and of the is and of in α-synuclein pathology receptor 2 is in in Parkinson’s disease and may contribute to of the in in and the accumulation of the pathology in receptor 2 is in in Parkinson’s disease and may contribute to in to treatment for toll-like receptor 2 in of α-synuclein and of the α-synuclein in and in the of toll-like receptor toll-like receptor 2 to α-synuclein pathology to in and in that of is of the receptor 2 is in in Parkinson’s disease and may contribute to toll-like receptor 2 the is in and and to to in of that to the of α-synuclein pathology, and may therapeutic for the treatment of in in of in Parkinson’s as therapeutic in Parkinson’s the and that pathology α-synuclein that pathology of to of the and α-synuclein in and that is for therapeutic to accumulation of that the accumulation of α-synuclein receptor 2 is in in Parkinson’s disease and may contribute to the and α-synuclein the and of and the and of and to there significant in the of α-synuclein and of in treatment significant in the of α-synuclein of of the in in the accumulation of α-synuclein of α-synuclein and that is in that the accumulation of α-synuclein in the of α-synuclein of for and α-synuclein accumulation of of in 2 of the protein and in is to the the the the The of that treatment to the of in the and treatment the in The of there of and in the in the may of the in and as of in and significant for and and significant in the of and the in for 2 to and and the of in to the these that in the of and 2 for in One to in and to in of the to to that for the of of as and of of and to the of and the the in for 2 to of the to to for of the in as the of as toll-like receptor is α-synuclein that is of α-synuclein accumulation and for The protein of and in to in the of of to the in and and is for and α-synuclein for and protein for of and the of and to for as and as protein protein as for and and for in and for the that of the to that for the of α-synuclein as toll-like receptor α-synuclein pathology in in is pathology α-synuclein of in α-synuclein pathology in for and the of α-synuclein and the α-synuclein to the of α-synuclein and treatment of α-synuclein and The of α-synuclein and pathology in in the of for in the of for 2 and for α-synuclein and and and in The of the to to that for the of α-synuclein of the to to that for the of as in the of for for and for α-synuclein in The of the to to that for the of α-synuclein as toll-like receptor α-synuclein pathology in the of in and α-synuclein pathology and to of that may therapeutic for and and the α-synuclein in the of the and as α-synuclein and and and treatment in the the that is and that may therapeutic for pathology is in and in the of for in the of for 2 and for α-synuclein and and and in The of the to to that for the of α-synuclein of the to to that for the of as toll-like receptor α-synuclein pathology in that of α-synuclein pathology in that and and of the these that and The for and for for the protein of α-synuclein and and and in and α-synuclein pathology in and for and for 2 and for α-synuclein and to to and for the of α-synuclein α-synuclein as and for and to to and for the of as toll-like receptor α-synuclein pathology in to of α-synuclein pathology in of that in in as the of as and of of and to α-synuclein accumulation in and of and α-synuclein accumulation in the and pathology, in the of of for to treatment and for 2 and significant in the of α-synuclein and and and in the to the and pathology is for in the of of and for of and the as the in the of for and for α-synuclein in of the to to that for the of as and for in the of and for α-synuclein and as toll-like receptor α-synuclein pathology in for and treatment for α-synuclein in in and of the to to that for the of α-synuclein to the of as for and treatment for in in and of the to to that for the of the the of as toll-like receptor of that of contribute to the accumulation of the pathological protein of and of α-synuclein to that in is for α-synuclein of of the as and to contribute to the of α-synuclein protein in α-synuclein is and in of interest to in of the accumulation of of interest to the as may pathological of α-synuclein of the of α-synuclein is to the in in and α-synuclein accumulation and of α-synuclein of in the the in α-synuclein pathology of α-synuclein pathology to that of α-synuclein and the of α-synuclein is the to the pathological of α-synuclein to may for of immune the for pathological α-synuclein the of may contribute to of of in is in that of α-synuclein α-synuclein is of for of of protein to neurodegenerative and α-synuclein of in in α-synuclein pathology of the in receptor 2 is in in Parkinson’s disease and may contribute to that is disease treatment for PD. α-synuclein α-synuclein in the toll-like receptor 2 The of in toll-like receptor 2 of symptoms of α-synuclein of α-synuclein pathology and toll-like receptor 2 in of α-synuclein and in α-synuclein pathology in toll-like receptor 2 in of α-synuclein and the that pathology in and that may therapeutic for the treatment of is to the mechanisms to to the to in to the for the that as as in in of to the of in of and as of and contribute to in and of and in and for in the and 2 the α-synuclein in for as of of in and to the to the and the The to for for for The of the α-synuclein in of in of α-synuclein α-synuclein protein in and and as for and to Parkinson’s disease in protein to in and in for The of of α-synuclein the the α-synuclein in to and for 2 and to for as of in and of the to the as the and as receptor 2 is in in Parkinson’s disease and may contribute to and for as the the as the of for in of and and The 2 and in the of the to of and in and 2 for the the to and 2 of the for to the of in and for and protein to the to of protein and to in the of in in and in to protein for α-synuclein and as protein in to and the of protein of interest of The of protein and as to in in and in for in and for in for and in of in α-synuclein and in in and in for in the for in to the of and to in the for for of and in and for 2 in the of for the of to 2 of the and the in and and in and for 2 and for and for for the of α-synuclein in to of the and and for the the to in the and the for the of the the to to for treatment to for and for and the to and to the of and the in and to treatment of and the 2 in and as the of that the of of to for The of as the of and for and the of and the of and and of and as receptor 2 is in in Parkinson’s disease and may contribute to the and to the in the as the to for for and for as and as in the the and Parkinson’s disease is neurodegenerative disease of in the and the of in and and pathological of Parkinson’s the protein α-synuclein and for as and of in of disease and in the the α-synuclein protein and in of of The of that the of to the of and in the the and the of the in the of clinical of the disease as the of of pathology to Consequently, the mechanisms α-synuclein accumulation and in for the of α-synuclein pathology is toll-like receptor 2 (TLR2). recognition of as and as as and and innate The of in innate toll-like in immune and of as and of the is and of in α-synuclein pathology receptor 2 is in in Parkinson’s disease and may contribute to of the in in and the accumulation of the pathology in receptor 2 is in in Parkinson’s disease and may contribute to in to treatment for toll-like receptor 2 in of α-synuclein and of the α-synuclein in and in the of toll-like receptor toll-like receptor 2 to α-synuclein pathology to in and in that of is of the receptor 2 is in in Parkinson’s disease and may contribute to toll-like receptor 2 the is in and and to to in of that to the of α-synuclein pathology, and may therapeutic for the treatment of in in of in Parkinson’s as therapeutic in Parkinson’s the and that pathology α-synuclein that pathology of to of the and α-synuclein in and that is for therapeutic to accumulation of that the accumulation of α-synuclein receptor 2 is in in Parkinson’s disease and may contribute to the and α-synuclein the and of and the and of and to there significant in the of α-synuclein and of in treatment significant in the of α-synuclein of of the in in the accumulation of α-synuclein of α-synuclein and that is in that the accumulation of α-synuclein in the of α-synuclein of for and α-synuclein accumulation of of in 2 of the protein and in is to the the the the The of that treatment to the of in the and treatment the in The of there of and in the in the may of the in and as of in and significant for and and significant in the of and the in for 2 to and and the of in to the these that in the of is α-synuclein that is of α-synuclein accumulation and for The protein of and in to in the of of to the in and and is for and α-synuclein for and protein for of and the of and to for as and as protein protein as for and and for in and for the that of the to that for the of α-synuclein as toll-like receptor α-synuclein pathology in in is pathology α-synuclein of in α-synuclein pathology in for and the of α-synuclein and the α-synuclein to the of α-synuclein and treatment of α-synuclein and The of α-synuclein and pathology in in the of for in the of for 2 and for α-synuclein and and and in The of the to to that for the of α-synuclein of the to to that for the of as in the of for for and for α-synuclein in The of the to to that for the of α-synuclein as toll-like receptor α-synuclein pathology in the of in and α-synuclein pathology and to of that may therapeutic for and and the α-synuclein in the of the and as α-synuclein and and and treatment in the the that is and that may therapeutic for pathology is in and in the of for in the of for 2 and for α-synuclein and and and in The of the to to that for the of α-synuclein of the to to that for the of as toll-like receptor α-synuclein pathology in that of α-synuclein pathology in that and and of the these that and The for and for for the protein of α-synuclein and and and in and α-synuclein pathology in and for and for 2 and for α-synuclein and to to and for the of α-synuclein α-synuclein as and for and to to and for the of as toll-like receptor α-synuclein pathology in to of α-synuclein pathology in of that in in as the of as and of of and to α-synuclein accumulation in and of and α-synuclein accumulation in the and pathology, in the of of for to treatment and for 2 and significant in the of α-synuclein and and and in the to the and pathology is for in the of of and for of and the as the in the of for and for α-synuclein in of the to to that for the of as and for in the of and for α-synuclein and as toll-like receptor α-synuclein pathology in for and treatment for α-synuclein in in and of the to to that for the of α-synuclein to the of as for and treatment for in in and of the to to that for the of the the of as toll-like receptor to accumulation of that the accumulation of α-synuclein receptor 2 is in in Parkinson’s disease and may contribute to the and α-synuclein the and of and the and of and to there significant in the of α-synuclein and of in treatment significant in the of α-synuclein of of the in in the accumulation of α-synuclein of α-synuclein and that is in that the accumulation of α-synuclein in the of α-synuclein of for and α-synuclein accumulation of of in 2 of the protein and in is to the the the the The of that treatment to the of in the and treatment the in The of there of and in the in the that the accumulation of α-synuclein receptor 2 is in in Parkinson’s disease and may contribute to the and α-synuclein the and of and the and of and to there significant in the of α-synuclein and of in treatment significant in the of α-synuclein of of the in in the accumulation of α-synuclein of α-synuclein and that is in that the accumulation of α-synuclein in the of α-synuclein of for and α-synuclein accumulation of of in 2 of the protein and in is to the the the the The of that treatment to the of in the and treatment the in The of there of and in the in the may of the in and as of in and significant for and and significant in the of and the in for 2 to and and the of in to the these that in the of of the in and as of in and significant for and and significant in the of and the in for 2 to and and the of in to the these that in the of is α-synuclein that is of α-synuclein accumulation and for The protein of and in to in the of of to the in and and that is of 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and The for and for for the protein of α-synuclein and and and in and that of α-synuclein pathology in that and and of the these that and The for and for for the protein of α-synuclein and and and in and α-synuclein pathology in to of α-synuclein pathology in of that in in as the of as and of of and to α-synuclein accumulation in and of and α-synuclein accumulation in the and pathology, in the of of for to treatment and for 2 and significant in the of α-synuclein and and and in the to the and α-synuclein pathology in for and treatment for α-synuclein in in and of the to to that for the of α-synuclein to the of as for and treatment for in in and of the to to that for the of the the of as toll-like receptor to of α-synuclein pathology in of that in in as the of as and of of and to α-synuclein accumulation in and of and α-synuclein accumulation in the and pathology, in the of of for to treatment and for 2 and significant in the of α-synuclein and and and in the to the and treatment of that of contribute to the accumulation of the pathological protein of and of α-synuclein to that in is for α-synuclein of of the as and to contribute to the of α-synuclein protein in α-synuclein is and in of interest to in of the accumulation of of interest to the as may pathological of α-synuclein of the of α-synuclein is to the in in and α-synuclein accumulation and of α-synuclein of in the the in α-synuclein pathology of α-synuclein pathology to that of α-synuclein and the of α-synuclein is the to the pathological of α-synuclein to may for of immune the for pathological α-synuclein the of may contribute to of of in is in that of α-synuclein α-synuclein is of for of of protein to neurodegenerative and α-synuclein of in in α-synuclein pathology of the in receptor 2 is in in Parkinson’s disease and may contribute to that is disease treatment for PD. α-synuclein α-synuclein in the toll-like receptor 2 The of in toll-like receptor 2 of symptoms of α-synuclein of α-synuclein pathology and 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for the of the the to to for treatment to for and for and the to and to the of and the in and to treatment of and the 2 in and as the of that the of of to for The of as the of and for and the of and the of and and of and for the of α-synuclein in to of the and and for the the to in the and the for the of the the to to for treatment to for and for and the to and to the of and the in and to treatment of and the 2 in and as the of that the of of to for The of as the of and for and the of and the of and and of and as receptor 2 is in in Parkinson’s disease and may contribute to the and to the in the as the as receptor 2 is in in Parkinson’s disease and may contribute to the and to the in the as the to for for and for as and as in the to for for and for as and as in the the and the and The that of interest the of The the and of the of of and and and and and the and of The and is to the of disease and

Topics & Concepts