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Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ’ s ataxia

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ABSTRACT

Frataxin (FXN) deficiency causes Friedreich’s ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

No MeSH data available.


Cellular senescence response in YG8R pancreas. (A) Pancreas slides from 24-month-old YG8R and C57BL/6J (WT) mice previously subjected to in situ SA-βgal staining (blue) and eosin staining (pink) were examined by bright-field microscopy. SA-βgal staining was restricted to islets of Langerhans. (B) Evaluation of SA-βgal-positive islets showed a higher percentage of YG8R islets compared with C57BL/6J. (C) Immunofluorescence with p19 ARF antibody was performed on slides of pancreas from both phenotypes and the signal intensity per defined area showed more intense signal in YG8R mice (D). (E) The distribution of the signal intensity of p19 ARF for each SA-βgal class of islets (positive or negative) confirmed cellular senescence in the pancreas. Values are expressed as mean±s.e.m.; ***P≤0.001 YG8R compared with WT. Scale bars: 50 μm.
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DMM024273F7: Cellular senescence response in YG8R pancreas. (A) Pancreas slides from 24-month-old YG8R and C57BL/6J (WT) mice previously subjected to in situ SA-βgal staining (blue) and eosin staining (pink) were examined by bright-field microscopy. SA-βgal staining was restricted to islets of Langerhans. (B) Evaluation of SA-βgal-positive islets showed a higher percentage of YG8R islets compared with C57BL/6J. (C) Immunofluorescence with p19 ARF antibody was performed on slides of pancreas from both phenotypes and the signal intensity per defined area showed more intense signal in YG8R mice (D). (E) The distribution of the signal intensity of p19 ARF for each SA-βgal class of islets (positive or negative) confirmed cellular senescence in the pancreas. Values are expressed as mean±s.e.m.; ***P≤0.001 YG8R compared with WT. Scale bars: 50 μm.

Mentions: The other tissue affected in FRDA is the pancreas. Analysis of histological sections of pancreas treated with X-gal solution showed a significant increase in SA-βgal activity in YG8R mice. The senescent phenotype was restricted to pancreatic islets of Langerhans (Fig. 7A). Almost 90% of YG8R islets were senescent, in comparison to 50% of WT islets (Fig. 7B). Thus, aging induced the senescence phenotype but senescence was much more evident in FXN-deficient YG8R islets of Langerhans. To confirm this finding we investigated the expression of p19ARF, an additional senescence marker. Raw intensity values of p19ARF were increased in the islets of YG8R mice versus WT (Fig. 7C,D). In addition, as shown in Fig. 7E, the SA-βgal-positive islets were significantly correlated with p19ARF expression in both phenotypes, confirming the senescence phenotype.Fig. 7.


Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ’ s ataxia
Cellular senescence response in YG8R pancreas. (A) Pancreas slides from 24-month-old YG8R and C57BL/6J (WT) mice previously subjected to in situ SA-βgal staining (blue) and eosin staining (pink) were examined by bright-field microscopy. SA-βgal staining was restricted to islets of Langerhans. (B) Evaluation of SA-βgal-positive islets showed a higher percentage of YG8R islets compared with C57BL/6J. (C) Immunofluorescence with p19 ARF antibody was performed on slides of pancreas from both phenotypes and the signal intensity per defined area showed more intense signal in YG8R mice (D). (E) The distribution of the signal intensity of p19 ARF for each SA-βgal class of islets (positive or negative) confirmed cellular senescence in the pancreas. Values are expressed as mean±s.e.m.; ***P≤0.001 YG8R compared with WT. Scale bars: 50 μm.
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Related In: Results  -  Collection

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DMM024273F7: Cellular senescence response in YG8R pancreas. (A) Pancreas slides from 24-month-old YG8R and C57BL/6J (WT) mice previously subjected to in situ SA-βgal staining (blue) and eosin staining (pink) were examined by bright-field microscopy. SA-βgal staining was restricted to islets of Langerhans. (B) Evaluation of SA-βgal-positive islets showed a higher percentage of YG8R islets compared with C57BL/6J. (C) Immunofluorescence with p19 ARF antibody was performed on slides of pancreas from both phenotypes and the signal intensity per defined area showed more intense signal in YG8R mice (D). (E) The distribution of the signal intensity of p19 ARF for each SA-βgal class of islets (positive or negative) confirmed cellular senescence in the pancreas. Values are expressed as mean±s.e.m.; ***P≤0.001 YG8R compared with WT. Scale bars: 50 μm.
Mentions: The other tissue affected in FRDA is the pancreas. Analysis of histological sections of pancreas treated with X-gal solution showed a significant increase in SA-βgal activity in YG8R mice. The senescent phenotype was restricted to pancreatic islets of Langerhans (Fig. 7A). Almost 90% of YG8R islets were senescent, in comparison to 50% of WT islets (Fig. 7B). Thus, aging induced the senescence phenotype but senescence was much more evident in FXN-deficient YG8R islets of Langerhans. To confirm this finding we investigated the expression of p19ARF, an additional senescence marker. Raw intensity values of p19ARF were increased in the islets of YG8R mice versus WT (Fig. 7C,D). In addition, as shown in Fig. 7E, the SA-βgal-positive islets were significantly correlated with p19ARF expression in both phenotypes, confirming the senescence phenotype.Fig. 7.

View Article: PubMed Central - PubMed

ABSTRACT

Frataxin (FXN) deficiency causes Friedreich’s ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

No MeSH data available.