Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism

Abstract

Down Syndrome (DS) is the most common genetic form of intellectual disability that leads in the majority of cases to development of early-onset Alzheimer-like dementia (AD). The neuropathology of DS has several common features with AD including alteration of redox homeostasis, mitochondrial deficits, and inflammation among others. Interestingly, some of the genes encoded by chromosome 21 are responsible of increased oxidative stress (OS) conditions that are further exacerbated by decreased antioxidant defense. Previous studies from our groups showed that accumulation of oxidative damage is an early event in DS neurodegeneration and that oxidative modifications of selected proteins affects the integrity of the protein degradative systems, antioxidant response, neuronal integrity and energy metabolism. In particular, the current review elaborates recent findings demonstrating the accumulation of oxidative damage in DS and we focus attention on specific deregulation of iron metabolism, which affects both the central nervous system and the periphery. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration; thus we opine that better understanding how and to what extent the concerted loss of iron dyshomeostasis and increased OS occur in DS could provide novel insights for the development of therapeutic strategies for the treatment of Alzheimer-like dementia.

Keywords: Iron; Oxidative stress; Protein oxidation; Redox proteomics; Trisomy 21.

Figure 1. Trisomy 21-induced oxidative stress

Schematic representation of a sub set of trisomic genes that are associate dwith increased oxidative stress (OS) conditions. In detail, SOD1, APP and BACH1 are the triplicated genes that are discussed in the review. SOD1 encodes for the enzyme superoxide dismutase; APP fort the amyloid precursor protein; and BACH1 for the transcription repressor BACH1 that bind to the antioxidant response elements (AREs) of DNA thus suppressing the induction of HO-1 and other antioxidant proteins. CAT=catalase; GPX= glutathione peroxidase; HO-1=heme oxygenase 1; BVR-A= biliverdin reductase A;

Figure 2. Schematic overview of the main iron metabolic pathways possibly involved in Down Syndrome neurodegeneration

In blue, proteins found to be altered in Down Syndrome. APP, amyloid precursor protein; BBB, blood brain barrier; CO, carbon monoxide; TFR-1/2, transferrin receptor-1/2;