A research
group led by Professor Michael Glickman, dean of Technion's Faculty of Biology,
has uncovered a key mechanism in the development of Alzheimer's. The mechanism
in question identifies toxic proteins and disposes of them.
In most cases, harmful proteins are degraded inside
the cell. However, the researchers found that in certain situations, the very
system meant to eliminate these proteins simply transfers them outside the
cell. This discovery may explain how a disease that begins randomly in
individual neurons can spread to large regions of the brain.
The study, published in Proceedings of the
National Academy of Sciences, was led by Prof. Glickman and postdoctoral
researcher Dr. Ajay Wagh. In their article, they describe how brain cells deal
with UBB+1, a defective and toxic variant of the protein ubiquitin.
The ubiquitin system is essential for breaking down
damaged and dangerous proteins. Ubiquitin helps the body eliminate such
proteins. The problem arises when ubiquitin mutates into UBB+1. Instead of protecting the cell, UBB+1 harms
it, forming protein aggregates associated with the development of Alzheimer's
disease. In brain cells, this damage is particularly severe because neurons do
not divide or regenerate—once a neuron dies, it cannot be replaced.
One of the "gatekeepers" that prevents UBB+1
from poisoning brain cells is the protein p62, which is involved in the
cellular self-cleaning process known as autophagy. Acting as a smart receptor, p62 recognizes UBB+1 and encloses it in a vesicle that prevents it
from causing harm.
Next, one of two things happens: p62 either directs
the vesicle to the lysosome, which is the cell's recycling center, or secretes it out of the cell
into the intercellular brain fluid. The Technion researchers show that the
second option may endanger brain tissue. Once the vesicle is expelled into the
brain's extracellular fluid, fragments of the toxic UBB+1 protein may leak into
neighboring neurons, thereby accelerating the spread of Alzheimer's pathology.
According to Prof. Glickman, "We all want someone to take out the trash, but in this case, the cells are dumping their trash on their neighbors. Although this solves an acute problem for the individual cell, it may cause long-term damage to the entire tissue. We believe that uncovering this mechanism will enable, first, early diagnosis of Alzheimer's disease based on analyses of cerebrospinal and other body fluids, and second, the development of precise, personalized treatments."
Source: Protein disposal system may accelerate Alzheimer's by transferring toxins between brain cells
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