Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition

Miwa, Hideto; Kubo, Takeji; Suzuki, Atsushi; Nishi, Katsunori; Kondo, Tomoyoshi

doi:10.1016/j.neulet.2005.01.024

Cited by 73 publications

(46 citation statements)

References 24 publications

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“…Described in the present manuscript substantial reduction of the striatal synapsin I -one of the most prominent neuron-specific phosphoproteins in the brain -observed 2 weeks after intraventricular administration of proteasome inhibitors, is in accordance with previous in vivo and in vitro studies which indicate that neurons are very sensitive to the depletion of proteasome function [2,4,17,28]. Because dopaminergic neurons are especially fragile to this depletion, and substantial loss of dopaminergic terminals in the striatum after proteasome inhibitors administration has been reported [15,28], we assume that observed synapsin I level decrease may reflect changes in population of striatal neurons and/or nigrostriatal terminals.…”

Section: Discussionsupporting

confidence: 91%

Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies

et al. 2015

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Section: Discussionsupporting

confidence: 91%

Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies

et al. 2015

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“…Previously, a body of genetic, postmortem and experimental evidence has converged to suggest that a failure of the UPS to degrade unwanted proteins might play a major role in the etiopathogenesis of both familial and sporadic forms of PD Olanow 2003:Petrucelli andDawson 2004). Several studies also reported that systemic administration of proteasome inhibitors can cause a progressive model of PD in rats (Fornai et al 2003;McNaught et al 2004;Miwa et al 2005;Schapira et al 2006). The findings suggest that PD is associated with an impaired capacity of the UPS to clear unwanted proteins.…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibitor Does Not Enhance MPTP Neurotoxicity in Mice

et al. 2008

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Dysfunction of the proteasome function is known to be a potential mechanism for dopaminergic neuron degeneration. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. PSI was injected into MPTP-treated mice over a period of 2 weeks. Thereafter, we evaluated the effect of PSI 2, 4, and 8 weeks after the cessation of treatment with PSI. In the present study with HPLC analysis, PSI did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Our present study with Western blot analysis also demonstrated that the reduction of tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) protein levels in MPTP-treated mice was more pronounced than that in MPTP + PSI-treated animals. These results suggest that proteasome inhibitor did not enhance MPTP neurotoxicity in mice. Our findings suggest that proteasome inhibition is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.

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“…The formation of Lewy bodies suggests that the ubiquitin-proteasome system (UPS) does not adequately clear misfolded or damaged proteins, leading to protein aggregation and culminating in degeneration of SN dopamine neurons. Consistent with this idea, proteasome inhibitors have been reported to cause dopamine cell death in vitro (McNaught et al, 2002;Petrucelli et al, 2002), and intrastriatal infusion of proteasome inhibitors results in the presence of α-synuclein-positive inclusions and degeneration of SN dopamine neurons (Fornai et al, 2003;Miwa et al, 2005). McNaught et al (2004) reported that systemic administration of the proteasome inhibitor Zlle-Glu(OtBu)-Ala-Leu-al (PSI) causes the progressive degeneration of nigrostriatal dopamine neurons and ubiquitinated, α-synuclein-immunoreactive (-ir) intracytoplasmic inclusions in surviving dopamine neurons, thus mimicking the pathology of PD.…”

Section: Introductionmentioning

confidence: 90%

Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration

et al. 2007

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Proteasomal dysfunction has been suggested to contribute to the degeneration of nigrostriatal dopamine neurons in Parkinson's disease. A recent study reported that systemic treatment of rats with the proteasome inhibitor Z-lle-Glu(OtBu)-Ala-Leu-al (PSI) causes a slowly progressive degeneration of nigrostriatal dopamine neurons, the presence of inclusion bodies in dopamine neurons, and motor impairment. We examined in vitro and in vivo the effects of PSI on nigrostriatal dopamine neurons. Mass spectrometric analysis was employed to verify the authenticity of the PSI compound. PSI was non-specifically toxic to neurons in ventral mesencephalic organotypic slice cultures, indicating that impairment of proteasome function in vitro is toxic. Moreover, systemic administration of PSI transiently decreased brain proteasome activity. Systemic treatment of rats with PSI did not, however, result in any biochemical or anatomical evidence of lesions of nigrostriatal dopamine neurons, nor were any changes in locomotor activity observed. These data suggest that systemic administration of proteasome inhibitors to normal adult rats does not reliably cause an animal model of parkinsonism.

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Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition

Cited by 73 publications

References 24 publications

Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies

Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies

Proteasome Inhibitor Does Not Enhance MPTP Neurotoxicity in Mice

Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration

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