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Intranigral Dopamine Toxicity and α-Synuclein Response in Rats

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Abstract

There is increasing evidence that, in addition to its function as the main neurotransmitter in the nigrostriatal pathway, dopamine (DA) may be neurotoxic in certain conditions. In this study, the toxicity of DA was assessed by direct injection into the substantia nigra of anaesthetised rats, and its effects were compared with those of 6-hydroxydopamine. Brains were removed 1, 2 and 3 weeks after the lesion for histological or neurochemical analysis. DA caused a significant loss of 35% of tyrosine hydroxylase-positive neurons in the pars compacta of substantia nigra and a 40% reduction of striatal DA content. Cells with signs compatible with both apoptosis and autophagy were observed. GADD153, a parameter of endoplasmic reticulum stress, was strongly induced by 6-hydroxydopamine but not by DA. DA increased the α-synuclein content 1 week after the lesion (but not at the later times analyzed) in tyrosine hydroxylase-positive and in non-dopaminergic fibers of pars reticulata. The α-synuclein increase may be a physiological temporal response to DA accumulation and/or to cell damage, but the simultaneous presence of α-synuclein and DA in the cell cytoplasm at concentration higher than normal is not exempt from risk. In fact, their incubation in a free cell system gives a stable dimerized form of α-synuclein that has been described as the critical rate-limiting step for its abnormal fibrillation.

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Acknowledgment

We thank the members of the Biochemistry, Neuropathology and Biology Unit (Serveis Científic-Tècnics of Campus Bellvitge) of the University of Barcelona. We are also grateful to Robin Rycroft for help with the English. This study was supported by the BFI 2003-02883, FIS 02/0004 and FIS-CIEN C-03006 grants from the Spanish Government and from the Fundació La Marató-TV3 (010310).

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Authors and Affiliations

  1. Centro Nacional de Investigación de Enfermedades Neurológicas-Bellvitge, Barcelona, Spain

    Cristina Gómez-Santos

  2. Departament de Patología i Terapèutica Experimental, IDIBELL, Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain

    Isidre Ferrer

  3. Unitat de Bioquímica, Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, c/Feixa Llarga s/n, E-08907–L’Hospitalet del Llobregat, Barcelona, Spain

    Pol Giménez-Xavier & Santiago Ambrosio

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  1. Cristina Gómez-Santos
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  4. Santiago Ambrosio
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Correspondence to Santiago Ambrosio.

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Gómez-Santos, C., Giménez-Xavier, P., Ferrer, I. et al. Intranigral Dopamine Toxicity and α-Synuclein Response in Rats. Neurochem Res 31, 861–868 (2006). https://doi.org/10.1007/s11064-006-9090-2

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