Publication Date:
2001-11-10
Description:
The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha-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 alpha-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha-synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conway, K A -- Rochet, J C -- Bieganski, R M -- Lansbury, P T Jr -- NS38375/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2001 Nov 9;294(5545):1346-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11701929" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antioxidants/pharmacology
;
Biopolymers/chemistry/metabolism
;
Catecholamines/pharmacology
;
Cytoplasm/metabolism
;
Dopamine/chemistry/*metabolism/pharmacology
;
Humans
;
Levodopa/pharmacology
;
Nerve Tissue Proteins/*chemistry/genetics/isolation & purification/*metabolism
;
Oxidation-Reduction
;
Oxidative Stress
;
Parkinson Disease/etiology/metabolism/therapy
;
Quinones/metabolism
;
Spectrometry, Fluorescence
;
Synaptic Vesicles/metabolism
;
Synucleins
;
alpha-Synuclein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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