Genome 2.0

The new study examines another area of risk for neurodegenerative illness, one bearing on an individual’s genes and how they are expressed. Although the 3 billion-letter DNA code making up an individual’s genome remains fixed throughout life, researchers now know that chemical messengers of great variety and complexity can act on the genome, delivering instructions to the DNA and guiding its behavior.

These epigenetic changes, as they are known, can turn genes on and off or regulate the amount of protein these genes produce. Earlier notions in biology emphasizing a static view of genomic destinies have given way to a new picture of life in which environmental changes can profoundly affect the way our genes behave. Scientists are just beginning to learn the far-reaching influence of the epigenome on human health and disease.

The current research describes epigenetic changes that take place in the brain when the level of the protein Rbbp7 is reduced, something the researchers detected in post-mortem brain tissue from Alzheimer’s patients.

One function of Rbbp7 is to regulate gene expression. It does this by altering the interaction of DNA with proteins known as histones, which DNA wraps around like sewing thread around a spool. When the DNA thread is loosely wrapped around the histone spool, the cell machinery can read the exposed DNA message and transcribe it into mRNA, which is then translated into protein. If the DNA thread is tightly wrapped around the histone however, the DNA genes are hidden from view and transcription maybe partially or entirely blocked, thereby reducing or disabling protein expression.

The researchers observed that when Rbbp7 levels are reduced, the level of another protein known as p300 increases, causing a post-translational modification of tau protein, known as acetylation. The effect of this is to cause tau protein to detach from cell structures known as microtubules, which tau typically binds with. The detached tau is then free to accumulate within neurons, eventually forming the telltale tangles associated with Alzheimer’s disease (see above graphic).

The acetylation of tau caused by low Rbbp7 results in increased phosphorylation of tau, further promoting tangle formation and subsequent neuronal loss in the brain.

In the new study, transgenic mice displaying tau pathology showed decreased levels of Rbbp7 and increased neuronal loss. Restoring Rbbp7 to normal levels in the mice reversed these pathologies, though the cognitive deficits remained.

Ramon Velazquez, assistant research professor at the ASU-Banner Neurodegenerative Disease Research Center and corresponding senior author of the new study, speculates that the reason for this is that the study targeted only a small subregion of the hippocampus, while other brain areas associated with cognition were still rampant with tangle formation. “We plan to look at the global effect of overexpressing Rbbp7 in our future research to see if we can rescue learning, memory and other facets of cognition,” he said.

Light at the end of the tunnel?

The associations outlined in the study between Rbbp7 levels and the formation of tau tangles, cell death and loss of cognitive function in the brain are compelling. The results suggest that Rbbp7 may be an attractive target for drug discovery and the development of effective therapies for Alzheimer’s disease and other tau-associated afflictions. Treatments based on studies of this kind could be ready for clinical trials within the next five years.

Nevertheless, the authors stress that other molecular players are likely involved in these complex processes. In future studies, the researchers plan to perform extensive, unbiased probing of protein interactions, transcription pathways from DNA to mRNA and the epigenetic modifications that can lead to neurodegenerative disease.

Richard Harth

Science writer, Biodesign Institute at ASU