Rifampicin reduces alpha-synuclein in a transgenic mouse model of multiple system atrophy - PubMed (original) (raw)

Rifampicin reduces alpha-synuclein in a transgenic mouse model of multiple system atrophy

Kiren Ubhi et al. Neuroreport. 2008.

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by oligodendrocytic cytoplasmic inclusions containing abnormally aggregated alpha-synuclein. This aggregation has been linked to the neurodegeneration observed in MSA. Current MSA treatments are aimed at controlling symptoms rather than tackling the underlying cause of neurodegeneration. This study investigates the ability of the antibiotic rifampicin to reduce alpha-synuclein aggregation and the associated neurodegeneration in a transgenic mouse model of MSA. We report a reduction in monomeric and oligomeric alpha-synuclein and a reduction in phosphorylated alpha-synuclein (S129) upon rifampicin treatment. This reduction in alpha-synuclein aggregation was accompanied by reduced neurodegeneration. On the basis of its anti-aggregenic properties, we conclude that rifampicin may have therapeutic potential for MSA.

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Figures

Fig. 1

Fig. 1

Rifampicin reduced α-syn accumulation in MBP-α-syn tg mice. Brightfield microscope images of α-syn immunoreactivity in vehicle-treated MBP-α-syn tg mice (a), rifampicin-treated MBP-α-syn tg mice (b), phosphorylated α-syn (S129) in vehicle-treated MBP-α-syn tg mice (d), rifampicin-treated MBP-α-syn tg mice (e), nitrosylated α-syn immunoreactivity in vehicle-treated MBP-α-syn tg mice (g), and rifampicin-treated MBP-α-syn tg mice (h). Confocal microscope images of α-syn immunoreactivity in vehicle-treated MBP-α-syn tg mice (j) and rifampicin-treated MBP-α-syn tg mice (k). Scale bars represent 50 μM (b, e, and h) and 100 μM (k). c, f, i, and l represent stereological analyses of the number of α-syn-immunoreactive neurons (polyclonal antibody), phosphorylated α-syn (S129), nitrosylated α-syn and monoclonal α-syn, respectively.*Significant difference between rifampicin-treated MBP-α-syn tg mice (_n_=10) in comparison with vehicle-treated MBP-α-syn mice (_n_=8) (P<0.05, one-way ANOVA and post-hoc Fisher). Alpha-syn, α-synuclein; ANOVA, analysis of variance; MBP, myelin basic protein.

Fig. 2

Fig. 2

Rifampicin reduced α-syn accumulation in MBP-α-syn tg mice. Western blot analysis of α-syn, phosphorylated α-syn (S129), nitrosylated α-syn, and β-syn. Actin was used as a loading control (a). All blots were loaded with protein from the detergent-insoluble fraction. (b–e) Analyses of immunoreactivity for monomeric α-syn, oligomeric α-syn, phosphorylated α-syn (S129), and nitrosylated α-syn, respectively. Immunoreactivity signal was normalized over Actin. *Significant difference between vehicle-treated MBP-α-syn tg mice (_n_=8) in comparison with vehicle-treated non-tg controls (_n_=8) (P<0.05, one-way ANOVA and post-hoc Fisher). **Signifcant difference between rifampicin-treated MBP-α-syn tg mice (_n_=10) in comparison with vehicle-treated MBP-α-syn tg mice (_n_=8) (P<0.05, one-way ANOVA and post-hoc Fisher). Alpha-syn, α-synuclein; ANOVA, analysis of variance; MBP, myelin basic protein.

Fig. 3

Fig. 3

Rifampicin reduced neurodegeneration in MBP-α-syn tg mice. Low-power confocal microscopic images of MAP2 immunoreactivity in vehicle-treated non-tg mice (a), vehicle-treated MBP-α-syn tg mice (b), and rifampicin-treated MBP-α-syn tg mice (c). Higher power confocal microscopic images of MAP2 immunoreactivity in vehicle-treated non-tg mice (d), vehicle-treated MBP-α-syn tg mice (e), and rifampicin-treated MBP-α-syn tg mice (f). Neocortical analysis of the area of the neuropil covered by MAP2 immunoreactivity was performed (g). Bright-field images of NeuN immunoreactivity in vehicle-treated non-tg mice (h), vehicle-treated MBP-α-syn tg mice (i) and rifampicin-treated MBP-α-syn tg mice (j) and GFAP immunoreactivity in vehicle-treated non-tg mice (l), vehicle-treated MBP-α-syn tg mice (m) and rifampicin-treated MBP-α-syn tg mice (n). Stereological analysis of NeuN immunoreactive neurons (k) and analysis of GFAP immunoreactivity (o). Scale bars represent 200 μM (a–c) and 50 μM (d–n). *Significant difference between vehicle-treated MBP-α-syn tg mice (_n_=8) in comparison with vehicle-treated non-tg controls (_n_=8) (P<0.05, one-way ANOVA and post-hoc Fisher). **Significant difference between rifampicin-treated MBP-α-syn tg mice (_n_=10) in comparison with vehicle-treated MBP-α-syn tg mice (_n_=8) (P<0.05, one-way ANOVA and post-hoc Fisher). ANOVA, analysis of variance; GFAP, glial fibrillary acidic protein; MBP, myelin basic protein.

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