New Risk Factors Discovered for Neurodegenerative Diseases

Scientists are beginning to believe that the origins of neurodegenerative disorders such as Alzheimer's disease are primarily caused by genes that are too active or not active enough, rather than by harmful gene mutations.

Mayo Clinic (Rochester, MN, USA) researchers measured the level of 24,526 transcripts (messenger RNA) for 18,401 genes using cerebellar autopsy tissue from 197 Alzheimer's disease patients and from 177 patients with other forms of neurodegeneration. They then validated the results by examining the temporal cortex from 202 Alzheimer's disease patients and from 197 with other pathologies. The difference between these samples is that while the temporal cortex is affected by Alzheimer's disease, the cerebellum is relatively spared.

More than 2,000 markers of altered expression in both groups of patients were identified that were common between the cerebellum and temporal cortex. Some of these markers also influenced risk of human diseases, suggesting that their contribution to development of neurodegenerative and other diseases is not related to their location in the brain.

They identified novel expression "hits" for genetic risk markers of diseases that included progressive supranuclear palsy, Parkinson's disease, and Paget's disease, and confirmed other known associations for lupus, ulcerative colitis, and type 1 diabetes.

"We now understand that disease likely develops from gene variants that have modest effects on gene expression, and which are also found in healthy people. But some of the variants—elevating expression of some genes, reducing levels of others—combine to produce a perfect storm that leads to dysfunction," said lead investigator Nilufer Ertekin-Taner, MD, PhD, a Mayo Clinic neurologist and neuroscientist.

"If we can identify the genes linked to a disease that are too active or too dormant, we might be able to define new drug targets and therapies," she said. "That could be the case for both neurodegenerative disease as well as disease in general."

In the June 7, 2012, online issue of PLoS Genetics, the scientists report that several hundred genes within almost 800 brain samples of patients with Alzheimer's disease or other disorders had altered expression levels that did not result from neurodegeneration. Many of those variants were likely the cause.

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