PMC:4731516 / 723-2422 JSONTXT

{"project":"TEST0","denotations":[{"id":"26858591-118-126-126980","span":{"begin":271,"end":275},"obj":"[\"9197268\"]"},{"id":"26858591-142-150-126981","span":{"begin":295,"end":299},"obj":"[\"14593171\"]"},{"id":"26858591-163-171-126982","span":{"begin":316,"end":320},"obj":"[\"15451225\"]"},{"id":"26858591-209-217-126983","span":{"begin":532,"end":536},"obj":"[\"9278044\"]"},{"id":"26858591-234-242-126984","span":{"begin":897,"end":901},"obj":"[\"15189334\"]"},{"id":"26858591-232-240-126985","span":{"begin":912,"end":916},"obj":"[\"16687141\"]"},{"id":"26858591-231-239-126986","span":{"begin":942,"end":946},"obj":"[\"23938255\"]"}],"text":"Alpha-synuclein in Parkinson's disease\nThe best-validated participant in the molecular pathology of Parkinson's disease (PD) is alpha-synuclein (α-syn). Mutations and multiplications of the α-syn SNCA gene locus both produce inherited forms of PD (Polymeropoulos et al., 1997; Singleton et al., 2003; Ibanez et al., 2004). In addition, the presence of α-syn in Lewy bodies and neurites of midbrain dopamine (DA) neurons, the histological hallmark of PD, provides evidence for its association with idiopathic PD (Spillantini et al., 1997). While a pervasive viewpoint postulates that excess α-syn and consequent aggregation directly fuels neurotoxicity in a toxic gain-of-function event, it also is acknowledged that α-syn aggregation may endanger neurons by removing the protein from its normal cellular location and diminishing its function in a toxic loss-of-function event (Perez and Hastings, 2004; Cookson, 2006; Kanaan and Manfredsson, 2012). This issue remains a topic of debate.\nDespite this ambiguity, approaches that may indiscriminately reduce α-syn in the central nervous system represent an active area of research as an approach for treating PD (e.g., AFFiRiS PD01, Prothena/Roche PRX002). In this Hypothesis and Theory article, we discuss evidence from rodent and non-human primate experiments suggesting that Parkinson's-like degeneration of the nigrostriatal DA system can be reproduced by eliminating endogenous α-syn from DA neurons vulnerable to degeneration in PD. These studies support the tentative conclusion that α-syn elimination therapies that do not distinguish between native and abnormal forms may compromise the viability of DA neurons and should proceed with caution."}

{"project":"0_colil","denotations":[{"id":"26858591-9197268-126980","span":{"begin":271,"end":275},"obj":"9197268"},{"id":"26858591-14593171-126981","span":{"begin":295,"end":299},"obj":"14593171"},{"id":"26858591-15451225-126982","span":{"begin":316,"end":320},"obj":"15451225"},{"id":"26858591-9278044-126983","span":{"begin":532,"end":536},"obj":"9278044"},{"id":"26858591-15189334-126984","span":{"begin":897,"end":901},"obj":"15189334"},{"id":"26858591-16687141-126985","span":{"begin":912,"end":916},"obj":"16687141"},{"id":"26858591-23938255-126986","span":{"begin":942,"end":946},"obj":"23938255"}],"text":"Alpha-synuclein in Parkinson's disease\nThe best-validated participant in the molecular pathology of Parkinson's disease (PD) is alpha-synuclein (α-syn). Mutations and multiplications of the α-syn SNCA gene locus both produce inherited forms of PD (Polymeropoulos et al., 1997; Singleton et al., 2003; Ibanez et al., 2004). In addition, the presence of α-syn in Lewy bodies and neurites of midbrain dopamine (DA) neurons, the histological hallmark of PD, provides evidence for its association with idiopathic PD (Spillantini et al., 1997). While a pervasive viewpoint postulates that excess α-syn and consequent aggregation directly fuels neurotoxicity in a toxic gain-of-function event, it also is acknowledged that α-syn aggregation may endanger neurons by removing the protein from its normal cellular location and diminishing its function in a toxic loss-of-function event (Perez and Hastings, 2004; Cookson, 2006; Kanaan and Manfredsson, 2012). This issue remains a topic of debate.\nDespite this ambiguity, approaches that may indiscriminately reduce α-syn in the central nervous system represent an active area of research as an approach for treating PD (e.g., AFFiRiS PD01, Prothena/Roche PRX002). In this Hypothesis and Theory article, we discuss evidence from rodent and non-human primate experiments suggesting that Parkinson's-like degeneration of the nigrostriatal DA system can be reproduced by eliminating endogenous α-syn from DA neurons vulnerable to degeneration in PD. These studies support the tentative conclusion that α-syn elimination therapies that do not distinguish between native and abnormal forms may compromise the viability of DA neurons and should proceed with caution."}

{"project":"2_test","denotations":[{"id":"26858591-9197268-38085257","span":{"begin":271,"end":275},"obj":"9197268"},{"id":"26858591-14593171-38085258","span":{"begin":295,"end":299},"obj":"14593171"},{"id":"26858591-15451225-38085259","span":{"begin":316,"end":320},"obj":"15451225"},{"id":"26858591-9278044-38085260","span":{"begin":532,"end":536},"obj":"9278044"},{"id":"26858591-15189334-38085261","span":{"begin":897,"end":901},"obj":"15189334"},{"id":"26858591-16687141-38085262","span":{"begin":912,"end":916},"obj":"16687141"},{"id":"26858591-23938255-38085263","span":{"begin":942,"end":946},"obj":"23938255"}],"text":"Alpha-synuclein in Parkinson's disease\nThe best-validated participant in the molecular pathology of Parkinson's disease (PD) is alpha-synuclein (α-syn). Mutations and multiplications of the α-syn SNCA gene locus both produce inherited forms of PD (Polymeropoulos et al., 1997; Singleton et al., 2003; Ibanez et al., 2004). In addition, the presence of α-syn in Lewy bodies and neurites of midbrain dopamine (DA) neurons, the histological hallmark of PD, provides evidence for its association with idiopathic PD (Spillantini et al., 1997). While a pervasive viewpoint postulates that excess α-syn and consequent aggregation directly fuels neurotoxicity in a toxic gain-of-function event, it also is acknowledged that α-syn aggregation may endanger neurons by removing the protein from its normal cellular location and diminishing its function in a toxic loss-of-function event (Perez and Hastings, 2004; Cookson, 2006; Kanaan and Manfredsson, 2012). This issue remains a topic of debate.\nDespite this ambiguity, approaches that may indiscriminately reduce α-syn in the central nervous system represent an active area of research as an approach for treating PD (e.g., AFFiRiS PD01, Prothena/Roche PRX002). In this Hypothesis and Theory article, we discuss evidence from rodent and non-human primate experiments suggesting that Parkinson's-like degeneration of the nigrostriatal DA system can be reproduced by eliminating endogenous α-syn from DA neurons vulnerable to degeneration in PD. These studies support the tentative conclusion that α-syn elimination therapies that do not distinguish between native and abnormal forms may compromise the viability of DA neurons and should proceed with caution."}