About one in every five people carries a version of a gene that, although largely unsung, appears to confer protection against both Alzheimer’s disease and Parkinson’s disease, Stanford Medicine investigators and their colleagues have learned. These lucky people may someday benefit all the more from a vaccine that could slow or stall the progression of these two most common neurodegenerative conditions.

An analysis of medical and genetic data from hundreds of thousands of people of diverse ancestries from several continents has revealed that carrying this gene version, or allele, reduced people’s chances of contracting either Parkinson’s or Alzheimer’s by more than 10% on average. 

The evidence suggests that a protein called tau, which is notorious for aggregating in the brains of Alzheimer’s patients, may also be involved, in some mysterious way, in the development of Parkinson’s disease.

The Stanford Medicine team combined dozens of medical and genetic databases collected from numerous countries — in Europe, East Asia, the Middle East, and South and North America. All told, the databases included more than 100,000 people with Alzheimer’s disease and more than 40,000 with Parkinson’s disease. The scientists contrasted the incidence and age of onset of Alzheimer’s and Parkinson’s among people with DR4 versus those without it and found a roughly 10% risk reduction in those carrying DR4.

The investigators 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 aggregates, composed largely of tau, that characterize Alzheimer’s disease — as well as a later onset of symptoms, than their non-DR4 counterparts. The presence of neurofibrillary tangles has been shown to correlate strongly with the condition’s severity.

Carrying DR4 also correlated with a later onset of symptoms in Parkinson’s patients, even though neurofibrillary tangles aren’t typically seen in that disease. 

This study hints that tau, an essential player in Alzheimer’s, may turn out to also play some kind of role in Parkinson’s, Mignot said, although what that role may be is not clear.

A cell’s surface is its display window:

DR4 is one among copious alleles of a gene called DRB1, which itself is one among many in a large complex of genes — called the human lymphocyte antigen complex, or HLA — that’s crucial to rendering cells’ inner contents visible to the immune system.

A cell’s outer membrane keeps the cell’s insides in and its outsides out. But that’s not all it does. It also serves as a display window, exposing fragments of the proteins inside it to the immune system. 

Routine exposure of these fragments, or peptides — stand-alone snippets of chopped-up proteins — on the cell’s surface (its outer membrane) allows roving immune cells to peruse them. By inspecting cell-surface peptides, these patrolling immune cells can see if there’s anything funny going on inside — namely, whether any foreign or altered protein might reside in the cell, implying an infection or cancerous state, respectively.

The tau connection?
Noting DR4’s beneficial effects on tau levels and pathologies in both Alzheimer’s and Parkinson’s, the researchers zeroed in on tau. They chopped molecules of the protein into 482 peptides collectively spanning tau’s entire sequence, then placed them into separate dishes along with DR4’s protein product (also called DR4) to see if it binds strongly to any of those peptides.

In addition, the researchers tested all the biologically likely chemical modifications each of those peptides can accrue once it’s been produced inside a cell.  

DR4 exerted an especially mighty grip on a single peptide. Called PHF6, this segment of the tau protein is frequently altered in the brains of Alzheimer's patients by a change called acetylation — the affixation of a small chemical clump to one of the protein’s constituent building blocks on that segment. Acetylated PHF6 has already been implicated in tau molecules’ tendency to aggregate into neurofibrillary tangles.

Source: lhttps://med.stanford.edu/news/all-news/2023/08/stanford-medicine-led-study-finds-genetic-factor-fends-off-alzhe.html