Limits...
Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1(G93A) Model of Amyotrophic Lateral Sclerosis.

Riancho J, Ruiz-Soto M, Villagrá NT, Berciano J, Berciano MT, Lafarga M - Front Cell Neurosci (2014)

Bottom Line: Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis.In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases.Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Service of Neurology, University Hospital Marqués de Valdecilla, Instituto de Investigación Valdecilla (IDIVAL), University of Cantabria , Santander , Spain.

ABSTRACT
We investigated neuronal self-defense mechanisms in a murine model of amyotrophic lateral sclerosis (ALS), the transgenic hSOD1(G93A), during both the asymptomatic and symptomatic stages. This is an experimental model of endoplasmic reticulum (ER) stress with severe chromatolysis. As a compensatory response to translation inhibition, chromatolytic neurons tended to reorganize the protein synthesis machinery at the perinuclear region, preferentially at nuclear infolding domains enriched in nuclear pores. This organization could facilitate nucleo-cytoplasmic traffic of RNAs and proteins at translation sites. By electron microscopy analysis, we observed that the active euchromatin pattern and the reticulated nucleolar configuration of control motor neurons were preserved in ALS chromatolytic neurons. Moreover the 5'-fluorouridine (5'-FU) transcription assay, at the ultrastructural level, revealed high incorporation of the RNA precursor 5'-FU into nascent RNA. Immunogold particles of 5'-FU incorporation were distributed throughout the euchromatin and on the dense fibrillar component of the nucleolus in both control and ALS motor neurons. The high rate of rRNA transcription in ALS motor neurons could maintain ribosome biogenesis under conditions of severe dysfunction of proteostasis. Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis. In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases. Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

(A,B) Electron micrographs of motor neurons from control (A) and hSOD1G93A mice (B). While control neuron exhibits numerous Nissl bodies throughout the cytoplasm (black asterisks), the ALS neuron shows a pale extensive chromatolytic area free of Nissl bodies. Note, however, that both neurons display large euchromatic nuclei with several interchromatin granule clusters (white asterisks) and a prominent nucleolus. W: whorl of RER. (C,D) Disruption of the protein synthesis machinery in ALS motor neurons from the hSOD1G93A mice. Note in (C), the partial detachment of polyribosomes from RER cisterns, with numerous polyribosomes scattered throughout the cytosol, and the focal dilations of cisterns (asterisks). (D) illustrates a cytoplasmic area with massive accumulation of RER-derived vesicles with remnants of membrane-bound ribosomes. (E,F) Whorl (E) and parallel (F) arrays of RER cisterns in motor neurons from hSOD1G93A mice. Note the presence of long segments with obliteration of the cisternal lumen and partial detachment of membrane-bound polyribosomes. Scale bars: (A,B) = 5 μm; (C,D) = 1 μm; (E) = 0.7 μm; (F) = 250 nm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4206191&req=5

Figure 2: (A,B) Electron micrographs of motor neurons from control (A) and hSOD1G93A mice (B). While control neuron exhibits numerous Nissl bodies throughout the cytoplasm (black asterisks), the ALS neuron shows a pale extensive chromatolytic area free of Nissl bodies. Note, however, that both neurons display large euchromatic nuclei with several interchromatin granule clusters (white asterisks) and a prominent nucleolus. W: whorl of RER. (C,D) Disruption of the protein synthesis machinery in ALS motor neurons from the hSOD1G93A mice. Note in (C), the partial detachment of polyribosomes from RER cisterns, with numerous polyribosomes scattered throughout the cytosol, and the focal dilations of cisterns (asterisks). (D) illustrates a cytoplasmic area with massive accumulation of RER-derived vesicles with remnants of membrane-bound ribosomes. (E,F) Whorl (E) and parallel (F) arrays of RER cisterns in motor neurons from hSOD1G93A mice. Note the presence of long segments with obliteration of the cisternal lumen and partial detachment of membrane-bound polyribosomes. Scale bars: (A,B) = 5 μm; (C,D) = 1 μm; (E) = 0.7 μm; (F) = 250 nm.

Mentions: Although previous studies have demonstrated the induction of chromatolysis with fragmentation of the RER in motor neurons of both ALS patients and murine models of ALS (Kusaka et al., 1988; Oyanagi et al., 2008; Sasaki, 2010), we have investigated the cellular basis of RER alterations that leads to translational inhibition in the mutant SOD1 mice. Electron microscopy of motor neurons showed a dense cytoplasm with numerous typical stacks of RER cisterns in control neurons in contrast to the pale cytoplasm produced by the paucity of RER elements in chromatolytic transgenic neurons (Figures 2A,B). Detailed ultrastructural analysis of RER showed two characteristic alterations. The first consisted of focal dilatations of the RER cisterns with partial detachment of membrane-associated polyribosomes that ultimately leads to fragmentation of the cisterns in numerous small cytoplasmic vesicles ranging in diameter from 200 to 500 nm (Figures 2C,D). The RER origin of these vesicles was also supported by the presence of remnants of polyribosomes attached to the cytosolic face of the membrane (Figure 2D). The accumulation of RER-derived vesicles is a common finding in chromatolytic areas of transgenic hSOD1G93A neurons. A second manifestation was the formation of whorl and stack arrays of RER containing collapsed cisterns with occlusion of the lumen (Figures 2E,F). Moreover, polyribosomes tended to be detached from collapsed cisterns, indicating that they are not engaged in active translations. This ultrastructural organization is distinct from the RER-derived lamellar bodies described in motor neurons of sporadic ALS patients (Sasaki, 2010). Taken together, these RER alterations reflect a severe disruption of the protein synthesis machinery.


Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1(G93A) Model of Amyotrophic Lateral Sclerosis.

Riancho J, Ruiz-Soto M, Villagrá NT, Berciano J, Berciano MT, Lafarga M - Front Cell Neurosci (2014)

(A,B) Electron micrographs of motor neurons from control (A) and hSOD1G93A mice (B). While control neuron exhibits numerous Nissl bodies throughout the cytoplasm (black asterisks), the ALS neuron shows a pale extensive chromatolytic area free of Nissl bodies. Note, however, that both neurons display large euchromatic nuclei with several interchromatin granule clusters (white asterisks) and a prominent nucleolus. W: whorl of RER. (C,D) Disruption of the protein synthesis machinery in ALS motor neurons from the hSOD1G93A mice. Note in (C), the partial detachment of polyribosomes from RER cisterns, with numerous polyribosomes scattered throughout the cytosol, and the focal dilations of cisterns (asterisks). (D) illustrates a cytoplasmic area with massive accumulation of RER-derived vesicles with remnants of membrane-bound ribosomes. (E,F) Whorl (E) and parallel (F) arrays of RER cisterns in motor neurons from hSOD1G93A mice. Note the presence of long segments with obliteration of the cisternal lumen and partial detachment of membrane-bound polyribosomes. Scale bars: (A,B) = 5 μm; (C,D) = 1 μm; (E) = 0.7 μm; (F) = 250 nm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206191&req=5

Figure 2: (A,B) Electron micrographs of motor neurons from control (A) and hSOD1G93A mice (B). While control neuron exhibits numerous Nissl bodies throughout the cytoplasm (black asterisks), the ALS neuron shows a pale extensive chromatolytic area free of Nissl bodies. Note, however, that both neurons display large euchromatic nuclei with several interchromatin granule clusters (white asterisks) and a prominent nucleolus. W: whorl of RER. (C,D) Disruption of the protein synthesis machinery in ALS motor neurons from the hSOD1G93A mice. Note in (C), the partial detachment of polyribosomes from RER cisterns, with numerous polyribosomes scattered throughout the cytosol, and the focal dilations of cisterns (asterisks). (D) illustrates a cytoplasmic area with massive accumulation of RER-derived vesicles with remnants of membrane-bound ribosomes. (E,F) Whorl (E) and parallel (F) arrays of RER cisterns in motor neurons from hSOD1G93A mice. Note the presence of long segments with obliteration of the cisternal lumen and partial detachment of membrane-bound polyribosomes. Scale bars: (A,B) = 5 μm; (C,D) = 1 μm; (E) = 0.7 μm; (F) = 250 nm.
Mentions: Although previous studies have demonstrated the induction of chromatolysis with fragmentation of the RER in motor neurons of both ALS patients and murine models of ALS (Kusaka et al., 1988; Oyanagi et al., 2008; Sasaki, 2010), we have investigated the cellular basis of RER alterations that leads to translational inhibition in the mutant SOD1 mice. Electron microscopy of motor neurons showed a dense cytoplasm with numerous typical stacks of RER cisterns in control neurons in contrast to the pale cytoplasm produced by the paucity of RER elements in chromatolytic transgenic neurons (Figures 2A,B). Detailed ultrastructural analysis of RER showed two characteristic alterations. The first consisted of focal dilatations of the RER cisterns with partial detachment of membrane-associated polyribosomes that ultimately leads to fragmentation of the cisterns in numerous small cytoplasmic vesicles ranging in diameter from 200 to 500 nm (Figures 2C,D). The RER origin of these vesicles was also supported by the presence of remnants of polyribosomes attached to the cytosolic face of the membrane (Figure 2D). The accumulation of RER-derived vesicles is a common finding in chromatolytic areas of transgenic hSOD1G93A neurons. A second manifestation was the formation of whorl and stack arrays of RER containing collapsed cisterns with occlusion of the lumen (Figures 2E,F). Moreover, polyribosomes tended to be detached from collapsed cisterns, indicating that they are not engaged in active translations. This ultrastructural organization is distinct from the RER-derived lamellar bodies described in motor neurons of sporadic ALS patients (Sasaki, 2010). Taken together, these RER alterations reflect a severe disruption of the protein synthesis machinery.

Bottom Line: Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis.In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases.Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Service of Neurology, University Hospital Marqués de Valdecilla, Instituto de Investigación Valdecilla (IDIVAL), University of Cantabria , Santander , Spain.

ABSTRACT
We investigated neuronal self-defense mechanisms in a murine model of amyotrophic lateral sclerosis (ALS), the transgenic hSOD1(G93A), during both the asymptomatic and symptomatic stages. This is an experimental model of endoplasmic reticulum (ER) stress with severe chromatolysis. As a compensatory response to translation inhibition, chromatolytic neurons tended to reorganize the protein synthesis machinery at the perinuclear region, preferentially at nuclear infolding domains enriched in nuclear pores. This organization could facilitate nucleo-cytoplasmic traffic of RNAs and proteins at translation sites. By electron microscopy analysis, we observed that the active euchromatin pattern and the reticulated nucleolar configuration of control motor neurons were preserved in ALS chromatolytic neurons. Moreover the 5'-fluorouridine (5'-FU) transcription assay, at the ultrastructural level, revealed high incorporation of the RNA precursor 5'-FU into nascent RNA. Immunogold particles of 5'-FU incorporation were distributed throughout the euchromatin and on the dense fibrillar component of the nucleolus in both control and ALS motor neurons. The high rate of rRNA transcription in ALS motor neurons could maintain ribosome biogenesis under conditions of severe dysfunction of proteostasis. Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis. In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases. Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus