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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

Coronal sections through the CA3 of the hippocampus of 4-month-old tbl/tbl mice. 1.5 μm thick sections show dark degenerative accumulations in the pyramidal cell somata (arrows in B). Condensed dark nuclei are occasionally observed within the pyramidal cell layer (arrowhead in B). Dark accumulations and vacuoles found throughout pyramidal cell cytoplasm have the same ultrastructural features (arrows in C–E) as those found in Purkinje cells and spinal motor neurons. Bars = 100 μm (A), 20 μm (B), 2 μm (C), and 1 μm (D–E).
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Figure 4: Coronal sections through the CA3 of the hippocampus of 4-month-old tbl/tbl mice. 1.5 μm thick sections show dark degenerative accumulations in the pyramidal cell somata (arrows in B). Condensed dark nuclei are occasionally observed within the pyramidal cell layer (arrowhead in B). Dark accumulations and vacuoles found throughout pyramidal cell cytoplasm have the same ultrastructural features (arrows in C–E) as those found in Purkinje cells and spinal motor neurons. Bars = 100 μm (A), 20 μm (B), 2 μm (C), and 1 μm (D–E).

Mentions: The electron microscopic study of tbl/tbl brain showed a similar morphological characteristics for the vacuoles accumulated in the cytoplasm of the neurons of the different brain areas analyzed. Features demonstrative of all the phases of the autophagic process—from early double-bounded autophagic vacuoles (autophagosomes) to dark final autolysosome (Clarke, 1990; Dunn, 1990a,b)—are observed within the cytoplasm of the cell bodies of Purkinje cells (Figures 1C–F), spinal cord motor neurons (Figure 3), CA3 pyramidal neurons (Figures 4C–E), and neocortical pyramidal neurons (Figures 5E–H, 6A–D), and within their dendritic trees (Figures 3A, 6A,E). In semithin sections these vacuoles are observed as dense dark points (Figures 1A,B, 2C–E,I, 4B, 5B–D). Other cellular organelles are consistently found, for example multivesicular bodies (Figure 3C) and healthy mitochondria intermingled with mitochondria showing different stages of degeneration such as the blurring and loss of their crests, and the progressive darkening of the mitochondrial matrices (Figures 1, 3, 4, 5, 6).


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)

Coronal sections through the CA3 of the hippocampus of 4-month-old tbl/tbl mice. 1.5 μm thick sections show dark degenerative accumulations in the pyramidal cell somata (arrows in B). Condensed dark nuclei are occasionally observed within the pyramidal cell layer (arrowhead in B). Dark accumulations and vacuoles found throughout pyramidal cell cytoplasm have the same ultrastructural features (arrows in C–E) as those found in Purkinje cells and spinal motor neurons. Bars = 100 μm (A), 20 μm (B), 2 μm (C), and 1 μm (D–E).
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Related In: Results  -  Collection

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Figure 4: Coronal sections through the CA3 of the hippocampus of 4-month-old tbl/tbl mice. 1.5 μm thick sections show dark degenerative accumulations in the pyramidal cell somata (arrows in B). Condensed dark nuclei are occasionally observed within the pyramidal cell layer (arrowhead in B). Dark accumulations and vacuoles found throughout pyramidal cell cytoplasm have the same ultrastructural features (arrows in C–E) as those found in Purkinje cells and spinal motor neurons. Bars = 100 μm (A), 20 μm (B), 2 μm (C), and 1 μm (D–E).
Mentions: The electron microscopic study of tbl/tbl brain showed a similar morphological characteristics for the vacuoles accumulated in the cytoplasm of the neurons of the different brain areas analyzed. Features demonstrative of all the phases of the autophagic process—from early double-bounded autophagic vacuoles (autophagosomes) to dark final autolysosome (Clarke, 1990; Dunn, 1990a,b)—are observed within the cytoplasm of the cell bodies of Purkinje cells (Figures 1C–F), spinal cord motor neurons (Figure 3), CA3 pyramidal neurons (Figures 4C–E), and neocortical pyramidal neurons (Figures 5E–H, 6A–D), and within their dendritic trees (Figures 3A, 6A,E). In semithin sections these vacuoles are observed as dense dark points (Figures 1A,B, 2C–E,I, 4B, 5B–D). Other cellular organelles are consistently found, for example multivesicular bodies (Figure 3C) and healthy mitochondria intermingled with mitochondria showing different stages of degeneration such as the blurring and loss of their crests, and the progressive darkening of the mitochondrial matrices (Figures 1, 3, 4, 5, 6).

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