National Institute of Health (October 16, 2018): A New Piece of the Alzheimer’s Puzzl

October 16, 2018

For the past few decades, researchers have been busy uncovering genetic variants associated with an increased risk of Alzheimer’s disease (AD) [1]. But there’s still a lot to learn about the many biological mechanisms that underlie this devastating neurological condition that affects as many as 5 million Americans [2].

As an example, an NIH-funded research team recently found that AD susceptibility may hinge not only upon which gene variants are present in a person’s DNA, but also how RNA messages encoded by the affected genes are altered to produce proteins [3]. After studying brain tissue from more than 450 deceased older people, the researchers found that samples from those with AD contained many more unusual RNA messages than those without AD.

The unusual messages apparently arose from changes in a normal process called RNA splicing. The flow of molecular information (otherwise known as the central dogma of molecular biology) goes from DNA to RNA to protein, but there are some important additional details. Forty years ago, we learned that the DNA instructions to make a human protein are often interrupted by “introns.” These introns are spacer sequences that are transcribed into RNA, but then must be spliced out before the mature messenger RNA is “ready for its close up” to be translated into protein by the ribosome.

RNA splicing doesn’t always happen in exactly the same way, depending on which introns are removed and which signals are used to direct the removal. When a particular RNA has multiple possible outcomes, it is called “alternative splicing.”

Though alternative RNA splicing is common throughout the body, it occurs at especially high frequency in the nervous system, including the brain [4]. Several years ago, researchers got their first hints that there may be altered splicing in AD and other forms of dementia [5].

In the new study, researchers led by Towfique Raj, Icahn School of Medicine at Mount Sinai, New York, and Philip De Jager, Columbia University, New York, wanted to take a more detailed look. Their goal was to generate a first comprehensive genome-wide map of splicing variation involving the prefrontal cortex. That’s the part of the brain involved in “executive functions,” such as planning and setting goals.