Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct
KA Conway, JC Rochet, RM Bieganski, PT Lansbury Jr - Science, 2001 - science.org
KA Conway, JC Rochet, RM Bieganski, PT Lansbury Jr
Science, 2001•science.orgThe substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and
contains fibrillar Lewy bodies comprising primarily α-synuclein. We screened a library to
identify drug-like molecules to probe the relation between neurodegeneration and α-
synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to
dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to α-
synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of …
contains fibrillar Lewy bodies comprising primarily α-synuclein. We screened a library to
identify drug-like molecules to probe the relation between neurodegeneration and α-
synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to
dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to α-
synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of …
The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily α-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and α-synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to α-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the α-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of α-synuclein–associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.
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