Abstract
Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability, and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy.
Highlights
Neurodegenerative PolyQ diseases are a group of relatively rare dominantly inherited disorders that are characterized by progressive and selective loss of neuronal cell bodies, dendrites and/or axons in the central nervous system
far infrared radiation (FIR) exposure decreased both endogenous and mutated ataxin-3 protein levels in contrary to the mRNA level of ATXN3 (Fig. 1c) in the MJD78 cells, whereas no significant effects were observed in the MJD26 cells (Fig. 1a,b)
We found no change in the total level of reactive oxygen species (ROS), nor in mitochondrial ROS, between the cell lines; the MJD78 cells demonstrated a significant increase in superoxide production and FIR did not protect against these effects (Fig. 1e)
Summary
Neurodegenerative PolyQ diseases are a group of relatively rare dominantly inherited disorders that are characterized by progressive and selective loss of neuronal cell bodies, dendrites and/or axons in the central nervous system. In common with the other neurodegenerative PolyQ diseases, the pathological mechanism of SCA3 involves aggregation of the mutated protein, mitochondrial dysfunction, cellular stress and cell death[4]. Mitochondria are organelles that play crucial roles in maintenance of cellular homeostasis and there is a clear link between mitochondrial dysfunction and neurodegenerative diseases[5] These organelles contribute a major part of cellular ATP via oxidative phosphorylation, which involves the electron transport chain (ETC) of protein complexes in the inner mitochondrial membrane. Any disturbance in this machinery typically leads to energy deficiency and/or production of reactive oxygen species (ROS), and thereby cellular stress and cell death[4]. The mechanisms of mitochondrial dynamics in neurodegenerative disorders are not completely understood, but are likely to involve common stress responses as well as specific interactions between mutated proteins and regulators of mitochondrial morphology[15]
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