Recently, scientists reported that certain human promoter sequences are more susceptible to age-related mutagenesis, suggesting that these somatic mutations may underlie many diseases of the elderly, including neurodegenerative disorders such as Alzheimer’s (see ARF related news story). Well, nuclear promoters may not be alone. In this week’s PNAS online, Douglas Wallace and Pinar Coskun at the University of California, Irvine, together with Flint Beal at Cornell University, New York, report that mutations in promoter regions of mitochondrial DNA are more common in people with AD.
The control region (CR) of the mitochondrial genome is the business end of this relatively small piece of DNA. Here, in just over 1,000 bases, reside several promoters, transcription factor binding sites, conserved sequence blocks (CSBs), and origins of replication. When Coskun tested postmortem frontal cortex samples, he found a higher incidence of CR mutations in samples taken from AD donors as compared to those from controls. This difference was statistically significant and was greater in older patients. Among those 80 and above, CR mutations were nearly 2.5 times higher in AD samples.
Could these mutations contribute to AD pathology—and how? Hints come from the location of the mutations. Not only are there more of them in AD samples, but they are also in more critical regions of the CR. In control samples, for example, most of the mutations occur between nucleotides 1 and 200, while most of the known functional sequences lie between nucleotides 200 and 570, which is where most of the AD sample mutations were. In CSB I, for example, Coskun found seven mutations in AD samples but none in control samples. Similar results were found for other key binding sites. The mutations may also affect mitochondrial number, and hence overall cellular fitness, because many of the mutations occurred in proximity to the PL region, a section of the genome that is necessary for transcription of the mitochondrial L-strand. As L-strand transcription is thought to be essential for replication of the genome, these mutations may prevent mitochondrial reproduction. In support of this, the authors found a 50 percent reduction in mtDNA copy number in AD samples.
These results also seem to point the finger, yet again, at reactive oxygen species (ROS) and mitochondrial damage as key players in neurodegeneration. “Once [CR] mutations arise,” write the authors, “they would become enriched in the postmitotic cells of the brain and ultimately result in mitochondrial oxidative phosphorylation deficiency, increased ROS production, activation of the mitochondrial permeability transition pore in the synaptic mitochondria, and loss of synaptic connections through apoptosis.—Tom Fagan
- Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. PubMed.