summary: Researchers have identified a gene allele, known as DR4, that provides a more than 10% reduction in the risk of Alzheimer’s and Parkinson’s disease. The study, which included hundreds of thousands of people of different ancestry, points to a possible role for tau in both conditions.
The DR4 allele triggers the immune system to target a specific part of the tau protein, which can disrupt the formation of harmful brain aggregates. This discovery opens the doors to targeted vaccines that could slow or even stop the progression of these neurodegenerative diseases.
- Identified through analysis of medical and genetic data of hundreds of thousands of people, the DR4 allele offers an approximately 10% lower risk of Alzheimer’s and Parkinson’s disease.
- The study points to a possible role for tau protein, which is well known in Alzheimer’s disease, in the development of Parkinson’s disease as well.
- The DR4 allele is considered a candidate for “protective autoimmunity,” because it leads the immune system to target a specific, disruptive form of the protein tau.
About one in five people carries a copy of the gene that appears to confer protection against Alzheimer’s and Parkinson’s disease, although it is largely unknown, Stanford medical researchers and colleagues know. These lucky people may one day benefit from a vaccine that can slow or even stop the progression of these two most common neurodegenerative conditions.
Analysis of medical and genetic data from hundreds of thousands of people of diverse origins from several continents revealed that carrying this gene copy, or allele, reduces the chances of developing Parkinson’s or Alzheimer’s disease by more than 10% on average.
Evidence suggests that a protein called tau, which is known to accumulate in the brains of Alzheimer’s patients, may also be involved, in a mysterious way, in the development of Parkinson’s disease.
The findings and their implications are described in a research paper published online August 29 in the journal Nature Proceedings of the National Academy of Sciences. Emmanuel Minot, MD, PhD, Craig Reynolds Professor of Sleep Medicine and Professor of Psychiatry and Behavioral Sciences, co-lead author with Michael Gracius, MD, Iqbal Farroukh and Asad Jamal Professor of Neuroscience and Neurosciences, and Jean-Charles Lambert, PhD Director of Inserm Research at the University of Lille, France. The lead authors are Yan Le Guin, Ph.D., associate director of computational biology in the Quantitative Sciences Unit at Stanford University of Medicine; Gu Luo, MD, instructor of sleep medicine; former postdoctoral researcher Aditya Ambati, Ph.D.; and Vincent Damot, Ph.D., a bioinformatics specialist associated with the Lambert Group.
The protective allele identified in the study is called DR4.
“In a previous study we found that carrying the DR4 allele appeared to protect against Parkinson’s disease,” Minnott said. “Now, we found a similar effect of DR4 on Alzheimer’s disease.”
The Stanford Medicine team combined dozens of medical and genetic databases collected from many countries – in Europe, East Asia, the Middle East, South and North America. In all, the databases included more than 100,000 people with Alzheimer’s disease and more than 40,000 people with Parkinson’s disease.
The scientists compared the incidence and age of onset of Alzheimer’s and Parkinson’s disease among people with DR4 versus those without, and found a risk reduction of nearly 10% in those with DR4.
“I was struck by the fact that this preventive agent for Parkinson’s disease has the same protective effect with regard to Alzheimer’s disease,” said Minnow. “The night after we found out, I couldn’t sleep.”
The researchers also analyzed data from the autopsied brains of more than 7,000 Alzheimer’s patients and found that DR4 carriers had fewer neurofibrillary tangles — long filamentous clumps, composed largely of the protein tau, that characterize Alzheimer’s disease — as well as fewer symptoms. later, compared with dissected brains. Their non-DR4 counterparts. The presence of neurofibrillary tangles has been shown to correlate strongly with the severity of the condition.
DR4 load is also associated with later onset of symptoms in Parkinson’s patients, although neurofibrillary tangles are not usually seen in this disease.
This study suggests that tau, a key player in Alzheimer’s disease, may also turn out to play some role in Parkinson’s disease, although this role may not be clear.
The surface of the cell is its viewing window
DR4 is one among the most prolific alleles of a gene called DRB1, itself one among many genes in a large complex of genes — called the human lymphocyte antigen complex, or HLA — that is critical to making the inner contents of cells visible to the immune system.
The outer cell membrane maintains the inner and outer parts of the cell. But that’s not all he does. It also serves as a window display, exposing parts of the proteins inside to the immune system.
Routine exposure of these fragments, or peptides–independent snippets of broken down proteins–to the cell surface (its outer membrane) allows circulating immune cells to view them.
By examining peptides on the cell surface, these patrolling immune cells can tell if there is anything strange going on inside, that is, if there is any foreign or altered protein present in the cell, implying the presence of an infection or a cancerous condition. , respectively.
Facilitating this shopping process are specialized proteins that can grab all of these peptides, package them, and present them on cell surfaces in a way that is ideal for immune recognition. These specialized proteins are products of the HLA genes.
Each of the many HLA genes comes in a wide range of alleles. Each of us inherits a different set of these alleles. Because different protein products of HLA alleles bind to different sets of peptides, the assortment of peptides that a person’s cells expose to immune surveillance varies from person to person.
When the immune system detects a surface peptide it thinks it has never seen before, it can launch a powerful attack on any cell that displays the peptide on its surface. Every now and then, the ruling turns out to be a case of mistaken identity. Autoimmunity is such a phenomenon.
Minot believes DR4 is involved in what’s called “protective autoimmunity”: The particular peptide that DR4 knows how to latch onto and display is actually a chemically modified part of the natural protein our cells make — tau. It’s the chemical modification that causes the problems.
Noting the beneficial effects of DR4 on tau levels and pathology in both Alzheimer’s and Parkinson’s disease, the researchers focused on tau. They cut the protein molecules into 482 peptides that collectively cover the entire tau sequence, then placed them in separate dishes with the DR4 protein product (also known as DR4) to see if it bound strongly to any of those peptides.
In addition, the researchers tested all the biologically possible chemical modifications that each of these peptides could accumulate once produced inside the cell.
DR4 exerted a particularly strong grip on one peptide. This part of the tau protein is called PHF6, and it is frequently altered in the brains of Alzheimer’s patients by a change called acetylation — the sticking of a small chemical block on one of the protein’s building blocks.
Acetylation of PHF6 has already been implicated in the tendency of tau molecules to aggregate into neurofibrillary tangles.
“The only peptide that binds strongly to DR4 is PHF6 — and that’s only when that peptide is acetylated,” Minnot said. He noted that acetylation of PHF6 is already known to facilitate tau aggregation at neurofibrillary tangles.
Acetylcholine may “trick” the immune system into thinking that PHF6 is foreign and dangerous, Minno said, leading the immune system to attack and destroy primary neurofibrillary tangles.
He believes it may be possible to make DR4 work more strongly in those who carry it by creating a vaccine consisting of acetylated PHF6. By drawing the immune system’s attention to this modified peptide, such a vaccine might interfere with tau buildup.
In people who carry any of the protective variants of DR4 (not all of them are protective) and whose brains have begun to accumulate tau aggregates, the vaccine could delay the onset of Alzheimer’s disease and possibly Parkinson’s disease or slow its progression, Minot suggested.
Minot noted that people who do not carry DR4 will not benefit from this vaccine. Furthermore, DR4 comes in a range of subtypes, which are characterized by minimal differences in their genetic sequences.
Of the six or seven most common subtypes of DR4, one type may be more common in people of the same bloodline, while others may be more common in people of other bloodlines. The DR4 subtype most common in East Asian populations does not seem to help stave off any neurodegenerative diseases as much as the DR4 subtypes that are more common in other populations do, for example.
Minno said a blood test should be done to find out who should or should not be vaccinated.
Stanford University’s Technology Licensing Office has filed a patent application on intellectual property related to the findings in this study.
About 160 additional researchers from many institutions in about 25 countries contributed to this work.
Funding: The study was funded by the National Institutes of Health (grants AG060747, AG066206, and AG066515), the European Union, the Michael J. Fox Foundation, the Alzheimer’s Association, the Iqbal Farooq and Asad Jamal Fund, the European Alzheimer’s DNA Biobank, and Japan. Agency for Medical Research and Development, the Einstein Center for Neurosciences in Berlin, the Swedish Research Council, the European Research Council, and Swedish state support for clinical research.
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author: Bruce Goldman
communication: Bruce Goldman – Stanford
picture: Image credited to Neuroscience News
Original search: Open access.
“Polysynthesis analysis of the HLA locus in Alzheimer’s and Parkinson’s disease reveals a co-adaptive immune response mediated by HLA-DRB1*04 subtypes.Written by Emmanuel Minot et al. Banas
Polysynthesis analysis of the HLA locus in Alzheimer’s and Parkinson’s disease reveals a co-adaptive immune response mediated by HLA-DRB1*04 subtypes.
Across multistrain populations, we analyzed human leukocyte antigen (HLA) associations in more than 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus.
HLA-specific micromapping showed the hierarchical protective effects of HLA-DRB1*04 subtypes representing the best, strongest association with HLA-DRB1*04:04 f Hala-DRB1*04:07 And the mediator is with Hala-DRB1*04:01 And Hala-DRB1*04:03.
The same signal has been associated with decreased neurofibrillary tangles in postmortem brains and has been associated with decreased levels of tau in cerebrospinal fluid and to a lesser extent with increased Aβ42.
protected Hala-DRB1*04 Subtypes are strongly associated with the aggregation-prone PHF6 tau sequence, but only upon acetylation of a lysine (K311), a common post-translational modification central to tau aggregation. that Hala-DRB1*04 The adaptive immune response reduces the risk of Parkinson’s disease and Alzheimer’s disease, possibly by acting against tau, offering potential therapeutic avenues.