Variant in immune gene may help protect against neurological diseases

Vaccinating people with variant could help delay or even prevent disease: study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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People with a specific variation in a gene that helps control the immune system are less likely to develop Parkinson’s disease and other neurological disorders, a new study reports.

Scientists think that people carrying this genetic variant might benefit from vaccines that could help to delay the progression of disease or even prevent neurological disease from developing.

The study, “Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes,” was published in PNAS.

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Genetics plays role in risk of neurological diseases

Although the causes of Parkinson’s remain incompletely understood, it’s well established that a person’s genetics play a sizeable role in determining the risk of Parkinson’s and many other neurological diseases.

In this study, scientists evaluated the relationship between disease risk and mutations in genes that encode parts of the human leukocyte antigen (HLA) protein complex.

The HLA complex acts like a display case on the surface of all cells in the body. Within cells, bits of proteins and other cellular materials are routinely placed in the HLA display, where they can be examined by immune cells. In this way, immune cells can frisk the contents of cells for signs of problems, like infection or cancer.

There are many different variations in HLA genes, which can affect what the immune system is able to “see” inside of cells. In the study, researchers found that a genetic variation in the HLA gene DRB1, known as the DR4 variant, is associated with a significantly lower risk of neurological disease. This variant is present in 20% to 30% of the population, with some variation among different ethnic groups.

The scientists analyzed data from tens of thousands of people with Parkinson’s, as well as many people without the disease, and they found that people carrying the DR4 variant were significantly less likely to have the disease, by around 10% on average.

A similar analysis of people with Alzheimer’s disease showed that people with DR4 were significantly less likely to have the disease. In both Parkinson’s and Alzheimer’s, people carrying the variant who did develop disease tended to do so at a later age.

“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me. The night after we found that out, I couldn’t sleep,” Emmanuel Mignot, MD, PhD, a professor at Stanford Medicine and co-author of the study, said in a press release.

A smaller analysis of people with amyotrophic lateral sclerosis found a similar trend, though results did not reach statistical significance, which researchers said was probably due to the smaller sample size.

The researchers next conducted a series of experiments hoping to understand why this HLA variant might help protect against neurological disease. They first analyzed brain samples from thousands of people with Alzheimer’s disease.

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Alzheimer’s patients with DR4 variant tended to have fewer toxic tau clumps

In Alzheimer’s, a protein called tau is known to form toxic clumps in the brain called neurofibrillary tangles, which damage nerve cells and are thought to play a major role in driving disease progression. The scientists found that Alzheimer’s patients carrying the DR4 variant tended to have fewer of these toxic protein clumps.

In further experiments, the researchers showed that, when the DR4 variant is present, the HLA complex is able to display a fragment of the tau protein called PHF6, but only if this protein fragment has undergone a type of molecular modification called acetylation. This modification of the PHF6 portion of the tau protein is thought to prompt tau to form toxic clumps.

“The only peptide [protein fragment] DR4 bound to strongly was PHF6 — and then only when this peptide was acetylated,” Mignot said.

That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me. The night after we found that out, I couldn’t sleep.

DR4 variant might help immune system to ‘see’ toxic tau

While tau has mainly been studied in Alzheimer’s, there’s some evidence that it also may play a role in Parkinson’s. The researchers found that the DR4 variant didn’t affect HLA’s ability to display fragments of alpha-synuclein, another protein that’s known to form toxic clumps in Parkinson’s.

Taking the findings collectively, the researchers think that the DR4 variant might help the immune system to “see” toxic tau. As a result, immune cells may become activated to clear out the toxic proteins, ultimately helping to reduce the risk of disease.

If this is the case, then it follows that a vaccination to activate the immune system against acetylated PHF6 might help in the treatment of these disorders, and could even help prevent disease from developing — but only in individuals who carry the specific variant. Theoretically, a blood test could be used to identify people most likely to benefit from such a vaccination, the researchers said.