Understanding the Biochemistry of Down Syndrome
Down syndrome is a multisystem disorder caused by the presence of a third copy, either total or partial, of chromosome 21. This genetic anomaly is associated with intellectual disability, visual problems, hearing impairments, seizures, dementia, cardiac and muscular complications, and gastrointestinal anomalies, among others.
Often, the pathophysiology and biochemistry underlying Down syndrome are not fully appreciated. What does it mean to interpret it from a biochemical perspective? It means viewing it as a metabolic disease.
Metabolic Alterations in Down Syndrome
Down syndrome presents an alteration in energy metabolism, which appears to be a significant determinant in the development of pathological phenotypes associated with the condition. For a chemical reaction to occur, we need a molecule called adenosine triphosphate (ATP). ATP is produced in the mitochondria, which then release ATP into the cells to facilitate various chemical reactions, including the conversion of proteins, amino acids, and vitamins—essentially, all the necessary reactions for proper cellular function.
However, in trisomy 21, there is a deficiency in the energy system. Many children with Down syndrome have impaired mitochondrial function, leading to various phenotypic differences. This mitochondrial dysfunction contributes to differences in developmental outcomes, such as speech abilities, muscular deficiencies, tendencies towards obesity or heart disease, and more. Chromosomes are composed of genes, and these genes are expressed in different ways.
Mitochondrial Dysfunction and Oxidative Stress
Mitochondrial defects in Down syndrome lead to increased oxidative stress and altered glucose and lipid metabolism. This results in reduced energy production and cellular dysfunction, depending on the genes expressed on the extra copy of chromosome 21.
Biochemical Approach to Down Syndrome
Interpreting Down syndrome from a biochemical standpoint is crucial for identifying new pharmacological targets and establishing preventive strategies to mitigate metabolic disorders and cognitive decline. It is known that over 200 genes on chromosome 21 encode proteins that can have direct and indirect effects on cellular, tissue, organ, and system homeostasis.
Functions of Key Genes
- Regulation of Oxidative Functions: Oxidative stress is an imbalance between oxidants and antioxidants in favor of oxidants, leading to disruption of redox signaling and control, and potential cellular damage.
- What is an Oxidant?
- A free radical is any chemical species containing one or more unpaired electrons in an atomic orbital.
Sources of Reactive Oxygen Species (ROS)
- Mitochondria
- Endoplasmic reticulum membranes
- Nuclear and plasma membranes
- Peroxisomes
- Cytosolic enzymes
Oxidative stress can result from decreased antioxidants and increased production of reactive species. This stress leads to cellular modifications. For instance, oxidation of carbohydrates, lipids, proteins, and nucleic acids (DNA and RNA) alters cellular function. Oxidized lipids can damage cell membranes, which are rich in lipids and phospholipids. Oxidation affects membrane structure and function, releases lipid oxidation products that can modify proteins and DNA, and impacts cellular integrity.
Implications of Lipid and Protein Oxidation
- Lipid Oxidation: Affects membrane structure and function, potentially releasing products that modify proteins and DNA.
- Protein Oxidation: Alters structure and function, increases susceptibility to proteolysis.
- Nucleic Acid Oxidation: Modifies DNA bases, causing cross-linking between DNA and proteins, and inducing mutagenesis.
Inhibition of Calcineurin
The enzyme calcineurin (PPP3C) or serine-threonine protein phosphatase 2B catalyzes the dephosphorylation of phosphoproteins and is calcium-dependent. Inhibiting calcineurin affects neuroreceptors involved in chemical compounds like dopamine, gamma-aminobutyric acid (GABA), and NMDA. This can lead to schizophrenia-like symptoms, impaired working memory, attention deficits, abnormal social behavior, and other abnormalities.
NMDA Receptors
NMDA receptors are cellular receptors in a subgroup (GluN) of ionotropic receptors. They play a crucial role in synaptic plasticity, learning, and memory.
Brain Structure in Down Syndrome
Individuals with Down syndrome show smaller brain volumes and reduced cortical surface area. Their brains exhibit decreased proliferation and differentiation capacities of neural progenitor cells (NPCs) and increased cell death. Oxidative stress damages cells by reducing proliferation and differentiation, leading to premature programmed cell death. Neurogenesis is thus deficient.
Conclusion
Down syndrome is not solely influenced by diet. It is essential to understand what is oxidized in the body. Addressing oxidative stress and mitochondrial dysfunction from a biochemical perspective is vital for developing effective treatments and improving the quality of life for those with Down syndrome.
