FXN

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Frataxin, mitochondrial precursor (EC 1.16.3.1) (Friedreich ataxia protein) (Fxn) [Contains: Frataxin intermediate form (i-FXN); Frataxin(56-210) (m56-FXN); Frataxin(78-210) (d-FXN) (m78-FXN); Frataxin mature form (Frataxin(81-210)) (m81-FXN)] [FRDA] [X25]

Publications[править]

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

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.

MeSH Terms

  • Aging
  • Animals
  • Axons
  • Cellular Senescence
  • Disease Models, Animal
  • Energy Metabolism
  • Friedreich Ataxia
  • Ganglia, Spinal
  • Humans
  • Insulin
  • Insulin Secretion
  • Insulin-Secreting Cells
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Muscles
  • Mutation
  • Oxidation-Reduction
  • Pancreas
  • Peripheral Nervous System

Keywords

  • Cell senescence
  • Dorsal root ganglia
  • Dying-back neuropathy
  • Friedreich’s ataxia
  • Islet of Langerhans
  • Muscle spindle


Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism.

Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG) are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca(2 ) homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.


Keywords

  • ER-stress
  • Friedreich ataxia
  • autophagy
  • calcium metabolism
  • cellular senescence
  • frataxin
  • mitochondrial dysfunction