Abstract
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 Ca2+ 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.
Highlights
Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia, with a prevalence of two to four individuals per 100,000 in Caucasian populations (Lopez-Arlandis et al, 1995; Vankan, 2013)
SILENCING OF FXN EXPRESSION INDUCES CELLULAR SENESCENCE BUT NOT APOPTOSIS To investigate the consequences of frataxin depletion in cells and mitochondria, we generated FXN -silenced clones of the human neuroblastoma SH-SY5Y cell line using five different shRNA targeted to five different sites on the FXN gene
In order to investigate the effects of a lack of frataxin on cellular homeostasis, we developed a cell model of frataxin deficiency by FXN gene silencing in the human neuroblastoma cell line SHSY5Y
Summary
Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia, with a prevalence of two to four individuals per 100,000 in Caucasian populations (Lopez-Arlandis et al, 1995; Vankan, 2013). Both the peripheral and central nervous systems are involved. FXN maps to chromosome 9q13 and encodes frataxin, a small protein of 210 amino acids (Campuzano et al, 1996) associated with the mitochondrial inner membrane (Babcock et al, 1997; Campuzano et al, 1997; Priller et al, 1997; Koutnikova et al, 1998). Pathophysiology of the disease is due to the reduced amount of frataxin in targeted neural and non-neural cells and tissues (Deutsch et al, 2010)
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