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HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

Ruiz R, Pérez-Villegas EM, Bachiller S, Rosa JL, Armengol JA - Front Neuroanat (2016)

Bottom Line: The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells.Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity.Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of SevilleSeville, Spain; Department of Physiology, Anatomy and Cell Biology, University Pablo de OlavideSeville, Spain.

ABSTRACT
The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

No MeSH data available.


Related in: MedlinePlus

Histograms of Beclin-1 (A,B), LC3 (C,D), and p62 (E,F) immunoreactivity densities through the CA3 hippocampus and frontal neocortex of 4-month-old wt mice (black bars), and the same brain regions of 4-month-old tbl/tbl mice (white bars). In the hippocampus the differences of immunoreactivity densities are not statistically significant (asterisks), being p > 0.5 for Beclin-1, p = 0.440 for LC3, and p = 0.397 for p62. In contrast, the differences of immunorectivity densities are statistically significant for the three autophagic cycle markers in the cerebral cortex (double asterisks; p = 0.019 for Beclin-1, p = 0.019 for LC3, and p = 0.017 for p62).
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Figure 10: Histograms of Beclin-1 (A,B), LC3 (C,D), and p62 (E,F) immunoreactivity densities through the CA3 hippocampus and frontal neocortex of 4-month-old wt mice (black bars), and the same brain regions of 4-month-old tbl/tbl mice (white bars). In the hippocampus the differences of immunoreactivity densities are not statistically significant (asterisks), being p > 0.5 for Beclin-1, p = 0.440 for LC3, and p = 0.397 for p62. In contrast, the differences of immunorectivity densities are statistically significant for the three autophagic cycle markers in the cerebral cortex (double asterisks; p = 0.019 for Beclin-1, p = 0.019 for LC3, and p = 0.017 for p62).

Mentions: The density of the immunoreactivity for the three markers of the autophagic cycle studied here showed different results according to the analyzed area. Thus, in the CA3 of the hippocampus although the densities of beclin-1 and p62 immunoreactivity were higher in tbl/tbl mice than in wt ones, their values were under the level of significance (Figures 10A,C,E). On the contrary, p values showed statistic significances in the frontal cortex for the immunoreactivity densities of the three markers, which were higher in tbl/tbl than in wt mice (Figures 10B,D,F). Although most detailed analyses by using western blot of each specific brain area are needed, present data reinforces the qualitative differences of the autophagic cell cycle observed in the mutation tambaleante.


HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

Ruiz R, Pérez-Villegas EM, Bachiller S, Rosa JL, Armengol JA - Front Neuroanat (2016)

Histograms of Beclin-1 (A,B), LC3 (C,D), and p62 (E,F) immunoreactivity densities through the CA3 hippocampus and frontal neocortex of 4-month-old wt mice (black bars), and the same brain regions of 4-month-old tbl/tbl mice (white bars). In the hippocampus the differences of immunoreactivity densities are not statistically significant (asterisks), being p > 0.5 for Beclin-1, p = 0.440 for LC3, and p = 0.397 for p62. In contrast, the differences of immunorectivity densities are statistically significant for the three autophagic cycle markers in the cerebral cortex (double asterisks; p = 0.019 for Beclin-1, p = 0.019 for LC3, and p = 0.017 for p62).
© Copyright Policy
Related In: Results  -  Collection

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Figure 10: Histograms of Beclin-1 (A,B), LC3 (C,D), and p62 (E,F) immunoreactivity densities through the CA3 hippocampus and frontal neocortex of 4-month-old wt mice (black bars), and the same brain regions of 4-month-old tbl/tbl mice (white bars). In the hippocampus the differences of immunoreactivity densities are not statistically significant (asterisks), being p > 0.5 for Beclin-1, p = 0.440 for LC3, and p = 0.397 for p62. In contrast, the differences of immunorectivity densities are statistically significant for the three autophagic cycle markers in the cerebral cortex (double asterisks; p = 0.019 for Beclin-1, p = 0.019 for LC3, and p = 0.017 for p62).
Mentions: The density of the immunoreactivity for the three markers of the autophagic cycle studied here showed different results according to the analyzed area. Thus, in the CA3 of the hippocampus although the densities of beclin-1 and p62 immunoreactivity were higher in tbl/tbl mice than in wt ones, their values were under the level of significance (Figures 10A,C,E). On the contrary, p values showed statistic significances in the frontal cortex for the immunoreactivity densities of the three markers, which were higher in tbl/tbl than in wt mice (Figures 10B,D,F). Although most detailed analyses by using western blot of each specific brain area are needed, present data reinforces the qualitative differences of the autophagic cell cycle observed in the mutation tambaleante.

Bottom Line: The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells.Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity.Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of SevilleSeville, Spain; Department of Physiology, Anatomy and Cell Biology, University Pablo de OlavideSeville, Spain.

ABSTRACT
The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

No MeSH data available.


Related in: MedlinePlus