Fight Aging!

A number of research groups are involved in the study of retrotransposons in the context of aging. These are genetic sequences that can copy themselves within the genome, and that activity increases with age. Linking this definitively to specific manifestations of aging is still to be accomplished, however. There are all the same challenges in making this connection as are inherent in proving that increased levels of stochastic nuclear DNA damage are a significant cause of dysfunction in aging beyond cancer risk. Correlations can be demonstrated, but evidence for causation is elusive. In the speculative research noted here, scientists investigate the behavior of retrotransposons in connection with the development of Alzheimer's disease:

The dominant idea guiding Alzheimer's research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause. This study builds on an alternative hypothesis. First proposed in 2004, the "mitochondrial cascade hypothesis" posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die. Like most human cells, neurons rely on mitochondria to stay healthy. But unlike other cells, most neurons stop dividing after birth, so they can't be replaced if they're damaged. In Alzheimer's patients, the thinking goes, the mitochondria in neurons stop working properly. As a result they are unable to generate as much energy for neurons, which starve and die with no way to replenish them. But how mitochondria in neurons decline with age is largely unknown.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, researchers identified a non-coding region in a gene called TOMM40 that varies in length. The team found that the length of this region can help predict a person's Alzheimer's risk and age of onset. The researchers wondered if the length variation in TOMM40 was only part of the equation. They analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer's-like symptoms with age. They found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus. Found only in primates, Alus belong to a family of retrotransposons or "jumping genes," which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, the researchers reasoned, they could help explain why mitochondria in nerve cells stop working.

When the researchers looked across the human genome, they found that Alus were more likely to be lurking in and around genes essential to mitochondria than in other protein-coding genes. Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to re-awaken. The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules - including the precursor to amyloid - to enter. Researchers used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria's import machinery to clog and stop working. The TOMM40 gene is one example, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS).

Link: https://today.duke.edu/2017/03/jumping-genes-suspected-alzheimers