Immune System Proteins Kill Synapses
Princeton University researchers have found that proteins of the major histocompatibility complex class I (major histocompatibility complex class I, MHC I), which perform important functions in the immune system, are responsible for both the "fine-tuning" of motor function control in the early stages of human development, and for the gradual extinction of muscle function as it ages. These data reveal the biological cause of the decline of muscle strength and deterioration of the sense of balance in the elderly, and also indicate possible approaches to combating this problem.
The immune function of proteins of the main histocompatibility complex of class I consists in binding to protein fragments or peptides and presenting them to T-lymphocytes. This presentation allows T-lymphocytes to recognize and destroy infected and malignant cells, on the surface of which complexes of MHC I proteins and abnormal or foreign peptides are expressed.
The authors, working under the guidance of Associate Professor Lisa Boulanger, found that proteins of the main histocompatibility complex of class I also play an important role in the formation of the nervous system. The expression of these proteins in neuromuscular synapses (areas of contact between the processes of neurons and muscle fibers) ensures the elimination of unnecessary synapses. This mechanism is triggered at the early stages of the development of the body, since at birth each muscle fiber of humans and other mammals receives signals from dozens of neuromuscular connections. However, for precise control over motor function, each muscle fiber must receive signals from only one motor neuron, so the elimination of unnecessary synapses at this stage is an important condition for the normal development of the body.
However, as it turned out, the expression levels of proteins of the main class I histocompatibility complex in neuromuscular synapses increase again in old age, contributing to the resumption of the process of removing neuromuscular connections, with the only difference that there are no extra synapses in a mature organism. This leads to a complete loss of innervation of individual muscle fibers, after which they can no longer participate in muscle contractions. As a result, the muscles of the elderly weaken, which makes them predisposed to health-threatening falls.
The authors explain that proteins of the main histocompatibility complex of class I are components of the immune system and their expression levels are expected to increase in inflammatory conditions. Aging is associated with chronic inflammation, which may explain the observed increase in the expression of these proteins and the reactivation of their earlier role.
The synapse of a 2-year-old (old) normal mouse is shown at the top right, the absence of superimposition of red and green fluorescent markers used to visualize cells in the area of contact between a neuron and a muscle fiber indicates denervation. At the bottom left is a full-fledged synapse with a pronounced area of overlapping markers.
At the same time, the authors demonstrated that a decrease in the expression levels of proteins of the main histocompatibility complex class I in mice generally prevents age-related denervation of muscle fibers.
In addition, it turned out that genetically modified mice with reduced levels of expression of proteins of the main histocompatibility complex of class I have "younger" profiles of muscle innervation. In fact, such animals were characterized by a deficiency of beta-2-microglobulin protein, which forms a complex with proteins of the main histocompatibility complex of class I and is necessary for their expression on the cell surface. The authors note that these data may be useful from a clinical point of view, since beta-2-microglobulin is water-soluble and its concentration in the blood can be reduced.
An image of the neuromuscular junction of a mouse model with reduced expression of proteins of the main histocompatibility complex of class I. Green is the color of two motor neurons connecting to one muscle fiber (red) at an age when only one connection should be preserved.
However, due to the important role of proteins of the main histocompatibility complex of class I in the work of the immune system, the use of such approaches can weaken the immune defense of the body. The mice lacking beta-2-microglobulin were characterized by a weakened immune system, which was due to the low expression of proteins of the main histocompatibility complex of class I. According to the authors, they plan to devote their future research to studying the effectiveness of other approaches that reduce the activity of these proteins aimed at destroying neuromuscular synapses, ideally without reducing immune function.
Article by Mazell M. Tetruashvily et al. MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction published in the journal Brain, Behavior, and Immunity.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Princeton University: Same immune-system proteins may first give, then take away motor control.
18.04.2016