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Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein.

Bentea E, Van der Perren A, Van Liefferinge J, El Arfani A, Albertini G, Demuyser T, Merckx E, Michotte Y, Smolders I, Baekelandt V, Massie A - Front Behav Neurosci (2015)

Bottom Line: Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration.Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder.We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel Brussels, Belgium.

ABSTRACT
Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturbances. Various pathogenic pathways drive disease progression including oxidative stress, mitochondrial dysfunction, α-synuclein aggregation and impairment of protein degradation systems. Dysfunction of the ubiquitin-proteasome system in the substantia nigra of Parkinson's disease patients is believed to be one of the causes of protein aggregation and cell death associated with this disorder. Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration. Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder. In order to further describe the proteasome inhibition model of Parkinson's disease, we characterized the unilateral lactacystin model, performed by stereotaxic injection of the toxin in the substantia nigra of mice. We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms. We report that unilateral administration of 3 μg lactacystin to the substantia nigra of mice leads to partial (~40%) dopaminergic cell loss and concurrent striatal dopamine depletion, accompanied by increased expression of Ser129-phosphorylated α-synuclein. Behavioral characterization of the model revealed parkinsonian motor impairment, as well as signs of non-motor disturbances resembling early stage Parkinson's disease including sensitive and somatosensory deficits, anxiety-like behavior, and perseverative behavior. The consistent finding of good face validity, together with relevant construct validity, warrant a further evaluation of proteasome inhibition models of Parkinson's disease in pre-clinical research and validation of therapeutic targets.

No MeSH data available.


Related in: MedlinePlus

Motor and somatosensory impairment in mice receiving 3 μg LAC. In the accelerating rotarod test, LAC lesioned mice showed decreased time spent on the rod, compared to sham mice receiving vehicle (A). In the cylinder test, LAC-treated mice engaged in significantly less right paw wall-contacts compared to sham mice (B). Also, LAC-treated mice had an increased preference to scan the cylinder walls more with their intact ipsilateral side (C). In the adhesive removal test, both time-to-contact (D), and the time required to remove the adhesive after detection (time-to-remove—time-to-contact) (E), were globally increased after LAC treatment compared to sham mice. Furthermore, in the nest building test, the nest score (F), as well as the amount of nesting material shredded (G), were globally decreased after LAC lesion, compared to sham mice. Data are presented as mean ± s.e.m. *p < 0.05, ***p < 0.001 (TwO-Way ANOVA), #p < 0.05, ##p < 0.01, ###p < 0.001 (Bonferroni post-hoc vs. sham). Sample size indicated in the figure. LAC lactacystin.
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Figure 4: Motor and somatosensory impairment in mice receiving 3 μg LAC. In the accelerating rotarod test, LAC lesioned mice showed decreased time spent on the rod, compared to sham mice receiving vehicle (A). In the cylinder test, LAC-treated mice engaged in significantly less right paw wall-contacts compared to sham mice (B). Also, LAC-treated mice had an increased preference to scan the cylinder walls more with their intact ipsilateral side (C). In the adhesive removal test, both time-to-contact (D), and the time required to remove the adhesive after detection (time-to-remove—time-to-contact) (E), were globally increased after LAC treatment compared to sham mice. Furthermore, in the nest building test, the nest score (F), as well as the amount of nesting material shredded (G), were globally decreased after LAC lesion, compared to sham mice. Data are presented as mean ± s.e.m. *p < 0.05, ***p < 0.001 (TwO-Way ANOVA), #p < 0.05, ##p < 0.01, ###p < 0.001 (Bonferroni post-hoc vs. sham). Sample size indicated in the figure. LAC lactacystin.

Mentions: First, we investigated the effect of the LAC lesion on motor function, using the accelerating rotarod task, a classical test used to assess motor coordination and balance in rodents bearing DA lesions. This paradigm is also believed to give indications of bradykinesia and/or limb rigidity, as the accelerating protocol requires fast and continuous adaptation of the mouse to increasing rod speeds (Sedelis et al., 2001). No significant differences could be observed in baseline performance in the training phase between groups (Supplementary Figure 2). After surgery, LAC-treated mice demonstrated decreased rotarod performance when compared to sham mice [treatment factor: F(1, 56) = 31.15, p < 0.001], an effect that could be significantly observed at both 1 week (p < 0.01) and 3 weeks (p < 0.001) post-lesion (Figure 4A).


Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein.

Bentea E, Van der Perren A, Van Liefferinge J, El Arfani A, Albertini G, Demuyser T, Merckx E, Michotte Y, Smolders I, Baekelandt V, Massie A - Front Behav Neurosci (2015)

Motor and somatosensory impairment in mice receiving 3 μg LAC. In the accelerating rotarod test, LAC lesioned mice showed decreased time spent on the rod, compared to sham mice receiving vehicle (A). In the cylinder test, LAC-treated mice engaged in significantly less right paw wall-contacts compared to sham mice (B). Also, LAC-treated mice had an increased preference to scan the cylinder walls more with their intact ipsilateral side (C). In the adhesive removal test, both time-to-contact (D), and the time required to remove the adhesive after detection (time-to-remove—time-to-contact) (E), were globally increased after LAC treatment compared to sham mice. Furthermore, in the nest building test, the nest score (F), as well as the amount of nesting material shredded (G), were globally decreased after LAC lesion, compared to sham mice. Data are presented as mean ± s.e.m. *p < 0.05, ***p < 0.001 (TwO-Way ANOVA), #p < 0.05, ##p < 0.01, ###p < 0.001 (Bonferroni post-hoc vs. sham). Sample size indicated in the figure. LAC lactacystin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4379937&req=5

Figure 4: Motor and somatosensory impairment in mice receiving 3 μg LAC. In the accelerating rotarod test, LAC lesioned mice showed decreased time spent on the rod, compared to sham mice receiving vehicle (A). In the cylinder test, LAC-treated mice engaged in significantly less right paw wall-contacts compared to sham mice (B). Also, LAC-treated mice had an increased preference to scan the cylinder walls more with their intact ipsilateral side (C). In the adhesive removal test, both time-to-contact (D), and the time required to remove the adhesive after detection (time-to-remove—time-to-contact) (E), were globally increased after LAC treatment compared to sham mice. Furthermore, in the nest building test, the nest score (F), as well as the amount of nesting material shredded (G), were globally decreased after LAC lesion, compared to sham mice. Data are presented as mean ± s.e.m. *p < 0.05, ***p < 0.001 (TwO-Way ANOVA), #p < 0.05, ##p < 0.01, ###p < 0.001 (Bonferroni post-hoc vs. sham). Sample size indicated in the figure. LAC lactacystin.
Mentions: First, we investigated the effect of the LAC lesion on motor function, using the accelerating rotarod task, a classical test used to assess motor coordination and balance in rodents bearing DA lesions. This paradigm is also believed to give indications of bradykinesia and/or limb rigidity, as the accelerating protocol requires fast and continuous adaptation of the mouse to increasing rod speeds (Sedelis et al., 2001). No significant differences could be observed in baseline performance in the training phase between groups (Supplementary Figure 2). After surgery, LAC-treated mice demonstrated decreased rotarod performance when compared to sham mice [treatment factor: F(1, 56) = 31.15, p < 0.001], an effect that could be significantly observed at both 1 week (p < 0.01) and 3 weeks (p < 0.001) post-lesion (Figure 4A).

Bottom Line: Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration.Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder.We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel Brussels, Belgium.

ABSTRACT
Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturbances. Various pathogenic pathways drive disease progression including oxidative stress, mitochondrial dysfunction, α-synuclein aggregation and impairment of protein degradation systems. Dysfunction of the ubiquitin-proteasome system in the substantia nigra of Parkinson's disease patients is believed to be one of the causes of protein aggregation and cell death associated with this disorder. Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration. Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder. In order to further describe the proteasome inhibition model of Parkinson's disease, we characterized the unilateral lactacystin model, performed by stereotaxic injection of the toxin in the substantia nigra of mice. We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms. We report that unilateral administration of 3 μg lactacystin to the substantia nigra of mice leads to partial (~40%) dopaminergic cell loss and concurrent striatal dopamine depletion, accompanied by increased expression of Ser129-phosphorylated α-synuclein. Behavioral characterization of the model revealed parkinsonian motor impairment, as well as signs of non-motor disturbances resembling early stage Parkinson's disease including sensitive and somatosensory deficits, anxiety-like behavior, and perseverative behavior. The consistent finding of good face validity, together with relevant construct validity, warrant a further evaluation of proteasome inhibition models of Parkinson's disease in pre-clinical research and validation of therapeutic targets.

No MeSH data available.


Related in: MedlinePlus