Could irregular gene splicing be responsible for Alzheimer’s progression?

The expression of genes encoded in DNA is responsible for almost the entirety of our body’s functioning.

However, the things we need to do—the proteins we need to make and the timing we need to coordinate—require many more genes than we have. One way that cells get around this is by splicing, or cutting, genes differently at different times to make new and different products. Now, research suggests that cutting genes incorrectly may be responsible for Alzheimer’s progression.

In a study published in Nature Genetics, Raj and colleagues investigate alternate splicing in Alzheimer’s patients. Previous research suggested that alternate splicing in certain specific genes might be linked to Alzheimer’s progression.

To confirm and expand on these findings, the researchers assessed DNA sequence and expression patterns in the brains of 450 individuals with and without Alzheimer’s and other kinds of dementia.

The researchers found that there were 53,251 alternate splicing sequences from 16,557 genes in individuals with an Alzheimer’s diagnosis at death. Of these, 82 alternate splicing sequences from 67 genes were associated with genes linked to nervous system pathologies, plaque, and other factors tied to Alzheimer’s progression.

Importantly, Raj and colleagues found that specific genes are affected in predictable patterns in association with Alzheimer’s progression, and that alternate splicing patterns affect genes that have previously been tied to Alzheimer’s risk.

Future work will need to further characterize the mechanism by which alternate splicing occurs. It is possible that alternate splicing is also involved in other diseases.

Regardless, this study opens up an important new target of treatment for preventing Alzheimer’s disease onset or Alzheimer’s progression, especially in combination with technologies such as CRISPR that can be used to target specific gene segments for novel therapies.

Reference: Raj et al. 2018. Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer’s disease susceptibility. Nature Genetics.