Humans normally have 23 pairs of chromosomes, but sometimes an error during cell division causes there to be an abnormal number of chromosomes. One of the most common chromosome abnormalities in humans is Down syndrome (DS). In most cases, this occurs when there is an extra copy of chromosome 21, which is called Trisomy 21. It is typically associated with distinct facial features, impaired cognitive functions, and stunted physical growth. Surprisingly, almost all people with DS also exhibit clinical symptoms of enfermedad de Alzheimer (AD) 10-20 years before it usually occurs in the general population. So, what is the link between DS and AD?
As Juan discussed last year, the accumulation of protein aggregates in the brain of people with Alzheimer’s disease impairs cellular metabolism at the mitochondria. Mitochondria, the “cellular power plants,” generate the majority of the energy currency of cells, adenosine triphosphate (ATP), which fuels many cellular activities. Dysfunction of mitochondria results in oxidative stress, which may in turn contribute to the ability of the cell to process the excess protein aggregates. It is possible that this might also be happening in the brain of people with Down syndrome?
Earlier this month, a team of researchers at UCI described how mitochondrial dysfunction and oxidative stress in DS patients cause them to be more susceptible to other conditions related to altered energy metabolism, such as Alzheimer’s disease. They found that mitochondria in DS cells exhibit increased fragmentation, meaning that they were much shorter than normal. This altered mitochondrial morphology caused a reduction in mitochondrial membrane potential, enzymatic activity, and ATP generation. In other words, DS cells are very energy deficient and are in a constant state of oxidative stress.
To test whether DS cells have the potential to restore normal mitochondrial function, the researchers artificially enhanced the metabolic stimulation of the mitochondria. This actually worked, and the function of the mitochondria was restored, but it increased the production of the metabolic byproducts called reactive oxygen species and it caused cell damage. This suggests that reduced DS mitochondrial activity is an adaptive response that helps avoid injury from oxidative stress and helps preserve basic cellular functions! Furthermore, the mitochondrial down-regulation seen in DS patients may explain why they are more susceptible to disorders that involve deficits in energy metabolism, such as Alzheimer’s disease.
While the underlying mechanisms of Down syndrome and Alzheimer’s disease are still unknown, this study helps uncover the link between mitochondrial dysfunction and oxidative stress in these conditions. Clearly a lot remains to be discovered!
~Pablo Helguera, Jaqueline Seiglie, Jose Rodriguez, Michael Hanna, Gustavo Helguera, Jorge Busciglio. Adaptive Downregulation of Mitochondrial Function in Down Syndrome. Cell Metabolism, 2013; 17 (1): 132 DOI:10.1016/j.cmet.2012.12.005 Images adapted from Science y Wikimedia Commons.