SIM2 Regulation of Mitochondrial Dysfunction in Down Syndrome

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SUMMARY Down Syndrome (DS) is the most common type of genetic disorder affecting approximately 1/750 newborns in the United States each year. DS is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). The DS phenotype is highly complex and variable including common phenotypes such characteristic facial features, intellectual disability, skeletal muscle weakness and variable phenotypes including heart defects, increased incidence of Alzheimer’s disease, type 2 diabetes and obesity. It is becoming clear that mitochondrial dysfunction and oxidative stress are major underlying factors in DS-related pathologies. Impairment in respiration, ATP production and mitochondria structure have been described in skeletal muscle and central nervous system in DS patients and mouse models. However, the mechanism driving mitochondrial dysfunction in DS is still not clear. We have shown that singleminded 2 (SIM2), a gene that was initially cloned on HSA21 and a member of the bHLH/PAS family of proteins, is expressed in skeletal muscle cells and regulates whole system metabolism. Our recent results using gain and loss function cell lines and mouse models have found that SIM2 regulates mitochondrial function, not as a classical transcription factor, but by interacting directly with mitochondria and modulating mitochondrial respiration (MRC), potentially through interaction with the mitochondria respiratory chain. Based on these new results, we hypothesize that increased expression of Sim2 in DS skeletal muscle promotes mitochondrial activity, resulting in increased oxidative stress and mitochondrial dysfunction. To address this hypothesis we propose three Specific Aims. In Aim 1, we will determine the role of SIM2 in the mitochondrial respiratory complex in DS. We will also define the physical basis for, and functional outcomes of, interactions between SIM2 and the mitochondria respiratory chain complex in metabolism. In Aim 2, we will determine the role of Sim2 in DS-associated skeletal muscle dysfunction by crossing the well- established DS mouse model, Dp(16)1Yey/+ DS, with whole body Sim2+/- knockout mice. In addition, we will also determine the impact loss of Sim2 has on mitochondrial turnover and structure by crossing the mito-QC mouse model with Sim2+/- mice. In Aim 3, we will take advantage of the recent advances in synthetic antisense oligonucleotide (ASO) technology to develop and test in cell culture and DS mouse models using a Sim2 ASO drug for DS. We expect results from these studies will help define the mechanism of mitochondrial dysfunction in DS.