Abstract
Superoxide dismutase 1 (SOD1) has been implicated with familial amyotrophic lateral sclerosis (fALS) through accumulation of protein amyloid aggregates in motor neurons of patients. Amyloid aggregates and protein inclusions are a common pathological feature of many neurological disorders in which protein aggregation seems to be directly related to neurotoxicity. Although, extensive studies performed on the aggregation process of several amyloidogenic proteins in vitro allowed the identification of many physiological factors involved, the molecular mechanisms underlying the formation of amyloid aggregates in vivo and in pathological conditions are still poorly understood. Post-translational modifications are known to affect protein structure and function and, recently, much attention has been devoted to the role played by non-enzymatic glycation in stimulating amyloid aggregation and cellular toxicity. In particular, glycation seems to have a determining role both in sporadic and familial forms of ALS and SOD1 has been shown to be glycated in vivo The aim of this study was to investigate the role of glycation on the amyloid aggregation process of both wild-type SOD1 and its ALS-related mutant G93A. To this aim, the glycation kinetics of both native and demetalated SOD have been followed using two different glycating agents, i.e., D-ribose and methylglyoxal. The effect of glycation on the structure and the amyloid aggregation propensity of native and ApoSOD has been also investigated using a combination of biophysical and biochemical techniques. In addition, the effect of SOD glycated species on cellular toxicity and reactive oxygen species (ROS) production has been evaluated in different cellular models. The results provided by this study contribute to clarify the role of glycation in amyloid aggregation and suggest a direct implication of glycation in the pathology of fALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a neurological disease causing the death of motor neurons and muscular paralysis
The proteins were incubated at 37◦C in the presence and in the absence of 0.5M D-ribose or 5 mM methylglyoxal and the samples were analyzed by Circular Dichroism (CD) spectroscopy at different time points (Figures 2, 3)
In order to follow changes in the secondary structure induced by glycation in human SOD and ApoSOD we monitored the dichroic activity in the far-UV region upon glycation
Summary
Amyotrophic Lateral Sclerosis (ALS) is a neurological disease causing the death of motor neurons and muscular paralysis. It is predominantly a sporadic disease, 10% of ALS cases are described as familial. Glycation Prevents Amyloid Aggregation in SOD1 containing superoxide dismutase in motor neurons of patients and transgenic model mice suggests that the aggregation of this protein is directly related to the pathology of fALS. It has been reported that some SOD1 mutants, many of them related to fALS (i.e., G93A) form soluble oligomeric species and that demetallation is the key factor for aggregation (Shaw and Valentine, 2007; Banci et al, 2008, 2009)
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