Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up‐regulate iHSP70, following proteasomal inhibition

Rideout, Hardy J.; Lang-Rollin, Isabelle; Savalle, Magali; Stefanis, Leonidas

doi:10.1111/j.1471-4159.2005.03124.x

Cited by 76 publications

(76 citation statements)

References 55 publications

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“…The percentage of apoptotic cells reaches 16% at a dose of 1µM and 23% at a dose of 5µM, which is similar to that of undifferentiated PC12 cells 11 and primary rat midbrain dopaminergic neurons 22 respectively. Although it is not a direct comparison, it may suggest at least that cholinergic cells are vulnerable to the proteasomal inhibition.…”

Section: Figure 2: Effect Of Lact On Mitochondrial Membrane Potentialsupporting

confidence: 55%

Proteasome Inhibitor Lactacystin Induces Cholinergic Degeneration

Zhou

Tan

Wang³

et al. 2010

Can. j. neurol. sci.

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The failure of ubiquitin proteasome (UP) function is widely believed to participate in the development of Parkinson's disease (PD) [1][2][3] . Recent studies have shown that most causative genes of familial PD are associated with ubiquitin proteasome system, including α-synuclein 4 , parkin 5 , ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) 6 and DJ-1 7 . Above all, evidence shows that proteasome inhibition has been found in the substantia nigra pars compacta (SNpc) of sporadic PD [8][9][10] , which accounts for 95 percent of all PD cases. All of these have triggered big interest in exploring the role of UP dysfunction in the pathogenesis of PD. Recently several studies have revealed that proteasome inhibitors could produce excellent PD animal models [11][12][13] , ABSTRACT: Objective: Ubiquitin proteasome system dysfunction is believed to play an important role in the development of Parkinson's disease (PD), and almost all studies till now have mainly focused on the susceptibility of dopaminergic neurons to proteasome inhibition. However, in fact, there are many other types of neurons such as cholinergic ones involved in PD. In our present study, we attempt to figure out what effect the failure of ubiquitin proteasome function would execute on cholinergic cells in culture. Methods:We treated cholinergic cells in culture with various doses of lactacystin. Then MTT assay was used to evaluate the cellular viability and the AnnexinV-PI method was used to detect apoptosis. Both cellular soluble and insoluble polyubiquitinated proteins were detected by western blot. Furthermore, the mitochondrial membrane potential was analyzed using JC-1 and the intracellular production of reactive oxygen species (ROS) was determined using the fluorescent probe CM-H2DCFDA. Results: We found that low doses of lactacystin were enough to induce significant apoptotic cell death, disturb the mitochondrial membrane potential, and cause oxidative stress. We also found that the amounts of polyubiquitinated proteins dramatically increased with high doses, although the loss of cells did not increase accordingly. Conclusions: Our results suggest that cholinergic cells are sensitive to ubiquitin proteasome system dysfunction, which exerts its toxic effect by causing mitochondrial dysfunction and subsequent oxidative stress, not through polyubiquitinated proteins accumulation.RÉSUMÉ: La lactacystine, un inhibiteur du protéasome, induit une dégénérescence cholinergique. Objectif : La dysfonction du système protéasome-ubiquitine jouerait un rôle important dans la genèse de la maladie de Parkinson (MP) et presque toutes les études ont ciblé la susceptibilité des neurones dopaminergiques à l'inhibition du protéasome. Cependant, il y a plusieurs autres types de neurones tels les neurones cholinergiques qui son impliqués dans la MP. Dans cette étude nous avons cherché à comprendre quelles sont les conséquences d'une dysfonction du système protéasome-ubiquitine sur des cellules cholinergiques en culture. Méthodes : Nous avons traité des cellules chol...

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Section: Figure 2: Effect Of Lact On Mitochondrial Membrane Potentialsupporting

confidence: 55%

Proteasome Inhibitor Lactacystin Induces Cholinergic Degeneration

Zhou

Tan

Wang³

et al. 2010

Can. j. neurol. sci.

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“…Consistent with this hypothesis, neurons exposed to proteasomal inhibitors or proteins prone to aggregation are more vulnerable to cell death (18)(19)(20). To test whether Snitrosylation of XIAP could comprise its ability to protect neurons against proteasomal dysfunction and protein aggregation, we treated cells with proteasomal inhibitor, MG132 (3 M), or expressed an aggregation-prone GFPu protein to induce cell death (21).…”

Section: Xiap S-nitrosylation Impairs Its Ability To Inhibit Caspase-mentioning

confidence: 89%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

141

112

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Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

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“…Several lines of evidence suggest that UPS dysfunction may be involved in the pathogenesis of PD (Dawson and Dawson, 2003;Dauer and Przedborski, 2003;Fornai et al, 2003Fornai et al, , 2005Singleton et al, 2003;Sawada et al, 2004;Rideout et al, 2005). In particular, it appears that UPS dysfunction coupled with other stressors, such as oxidative stress and mitochondrial inhibition, is toxic to nigrostriatal dopamine neurons (Giasson et al, 2000;Hoglinger et al, 2003;Elkon et al, 2004;Betarbet et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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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Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up‐regulate iHSP70, following proteasomal inhibition

Cited by 76 publications

References 55 publications

Proteasome Inhibitor Lactacystin Induces Cholinergic Degeneration

Proteasome Inhibitor Lactacystin Induces Cholinergic Degeneration

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

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

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