Frataxin deficiency causes Friedreich 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, patients are affected by 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 posterior columns and brain, which agree with the existence of a dying back process similar to described in FRDA patients. In YG8R 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 cell may underlay the nerve pathology. In pancreas we found high proportion of senescent islets of Langerhans in YG8R mice that makes the β cell number and islet mass decrease to pathological levels, since they are unable to maintain normoglycemia. As a whole, these results confirm that the lack of frataxin induces different pathogenic mechanisms in nervous system and pancreas in the mouse model of FRDA: sensory nerve dying-back and pancreatic senescence.
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