Proteasome Inhibitors Protect Against Degeneration of Nigral Dopaminergic Neurons in Hemiparkinsonian Rats

Inden, Masatoshi; Kondo, Junichi; Kitamura, Yoshihisa; Takata, Kazuyuki; Nishimura, Kaneyasu; Taniguchi, Takashi; Sawada, Hideyuki; Shimohama, Shun

doi:10.1254/jphs.fp0040525

Cited by 46 publications

(38 citation statements)

References 39 publications

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“…Furthermore, low-level of PSI exposure to SH-SY5Y cells was protective against serum withdrawal and oxidative stress (44). Together with the results by Inden et al (28) and Sawada et al (32) using PSI at low doses, the recent publications give us a cue to refine the link between UPS and the mechanisms of DA cell death. The effect of UPS inhibition might be harmful or beneficial, depending on the level of inhibition and other factors involved in DA cell maintenance.…”

mentioning

confidence: 60%

Does Proteosome Inhibition Decrease or Accelerate Toxin-Induced Dopaminergic Neurodegeneration?

Setsuie¹,

Kabuta²,

Wada³

2005

J Pharmacol Sci

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Abstract. Parkinson's disease (PD) is pathologically characterized by dopaminergic (DA) cell death and the presence of Lewy bodies (LB) in the brain. a -Synuclein (a-syn) and ubiquitin (Ub) are the major components of LB, however, the process of their accumulation and their relationship to DA cell loss has not yet been resolved. Now, in this journal, Inden et al. showed the protective effect of proteasome inhibitors (PSI) on DA cell death in the rat PD model using 6-hydroxyl dopamine (6-OHDA). Co-administration of PSI, lactacystin, or MG-132 significantly prevented the nigral degeneration and apomorphine-induced rotational asymmetry of the model with increased appearance of a -syn-and Ub-positive inclusions in the substantia nigra. This study indicates that in their model, accelerated formation of inclusions via proteasome inhibition protects against DA cell death. Previous literature linked the impairments or inhibitions of the ubiquitin-proteasome system (UPS) and DA cell death. However, this report implies that the relationship between the UPS and the pathogenesis of PD may be more complex than we thought.

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mentioning

confidence: 60%

Does Proteosome Inhibition Decrease or Accelerate Toxin-Induced Dopaminergic Neurodegeneration?

Setsuie¹,

Kabuta²,

Wada³

2005

J Pharmacol Sci

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“…Although in vitro studies have found that UPS inhibitors can cause dopamine cell death, there has been a lack of data indicating that systemic treatment with UPS inhibitors alone causes specific dopamine neuron toxicity. In sharp contrast to in vitro studies, Inden et al (2005) suggested that proteasomal inhibition may afford protection against 6-hydroxydopamine-induced SN cell loss, suggesting that the role of proteasomal inhibition in dopamine cell loss is likely to be more complex than initially envisioned (see Setsuie et al, 2005). …”

Section: Discussionmentioning

confidence: 93%

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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“…Microscopically, proteinacious inclusions, termed "Lewy bodies" (LBs) are frequently detected in remaining nigral neurons of postmortem PD brains. The presence of these cytoplasmatic inclusions might be cytotoxic (Hurtig et al, 2000;Giasson et al, 2002;Braak et al, 2004), but there is increasing evidence that, in contrast, they might be cytoprotective by sequestering toxic protein structures (Gispert et al, 2003;Tanaka et al, 2004;Inden et al, 2005;Bodner et al, 2006). ␣-Synuclein (␣-syn) was identified as the major filamentous component of LBs (Spillantini et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

165

134

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␣-Synuclein (␣-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether ␣-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type ␣-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting ␣-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, ␣-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.

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Proteasome Inhibitors Protect Against Degeneration of Nigral Dopaminergic Neurons in Hemiparkinsonian Rats

Cited by 46 publications

References 39 publications

Does Proteosome Inhibition Decrease or Accelerate Toxin-Induced Dopaminergic Neurodegeneration?

Does Proteosome Inhibition Decrease or Accelerate Toxin-Induced Dopaminergic Neurodegeneration?

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

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

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