Mechanotransduction and its Role in Neurodegenerative Diseases

Review from the University of Perugia summarizes current research

Mechanotransduction refers to biological processes in which cells take up mechanical stimuli from their environment and convert them into biochemical signals. This conversion enables cells to respond to changes in their mechanical environment and act accordingly.

These processes play an important role in various biological functions and processes, including cell growth, differentiation, migration, and tissue regeneration. Mechanotransduction is also involved in the perception of touch and pressure in the nervous system. Mechanotransduction involves various cellular components such as receptors, ion channels, and the cytoskeleton. When a cell is exposed to a mechanical stimulus, these components can change, leading to a cascade of intracellular events that eventually triggers a cellular response. This response can be in the form of, for example, changes in gene expression, activation of signaling pathways, or release of molecules.

Overall, mechanotransduction is a complex and multifaceted process that is essential for maintaining the normal function of tissues and organs in the human body-and can be used therapeutically.

Basic functions of mechanotransduction: significant progress in understanding the processes

In recent years, considerable progress has been made in understanding mechanotransduction. However, there are still many aspects of this process that are not fully understood. One reason is that mechanotransduction occurs in different ways in different cell types and tissues and can be influenced by a variety of mechanical stimuli. These stimuli can originate from the cell itself (autocrine), from neighboring cells (paracrine), or from the wider environment (endocrine). The way cells respond to these stimuli can also be influenced by the state of the cell, its environment, and genetic factors.

In this context, it is difficult to accurately measure and manipulate the mechanical forces acting on cells. In addition, many of the molecular components involved in mechanotransduction have only been discovered in recent years, and their precise functions and interactions are therefore not yet fully understood.

However, despite these challenges, researchers have made important discoveries about mechanotransduction, and there are active areas of research focused on further elucidating the mechanisms and functions of mechanotransduction. This research has the potential to open up or explain new approaches to the treatment of various diseases and conditions in which mechanotransduction plays a role.

Transcranial pulse stimulation (TPS), a neurostimulation technique based on low-energy shock waves, also exploits the properties of mechanotransduction to influence the progression of neurodegenerative diseases such as Alzheimer’s dementia.

Role of neurodegenerative disease pathogenesis comprehensively illuminated

Recent advances in the characterization of biochemical mechanosensing and mechanotransduction pathways in cells, with particular attention to their role in the pathogenesis of neurodegenerative diseases, have been highlighted by a research team led by study leader Illaria Tortorella of the University of Perugia, Italy. In a comprehensive review, the scientists:recapitulate the general concepts of mechanobiology and the mechanisms underlying mechanosensing and mechanotransduction processes, and examine the interactions between mechanical stimuli and intracellular biochemical responses, highlighting their effects on cellular organelle homeostasis and dysfunction.

The researchers note that the mechanistic components are now largely elucidated, but the interplay between mechanical forces and soluble intracellular signals is still not fully understood.

In this discussion, the research team focuses primarily on elucidating the current state of knowledge regarding the conversion of mechanical to biochemical signals, particularly in the context of diseases characterized by metabolic accumulation of misfolded proteins with the formation of pathological intracellular aggregates as a major feature. This is true for diseases such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.

Recent research findings clearly indicate that mechanosensing and mechanotransduction processes are critical for understanding the pathological mechanisms underlying neurodegenerative diseases. Moreover, they highlight the relevance of these processes for finding potential therapeutic targets.

Meanwhile, mechanobiological alterations at different cellular levels have been identified in the context of Alzheimer’s disease, leading to new avenues of research on these signaling pathways in the fight against Alzheimer’s disease.

Scientists believe that mechanosensitive ion channels play a key role in this process. Mechanotransduction is thought to lead to an increase in cell permeability, as well as altering the concentration of neurotransmitters (increasing serotonin and dopamine, decreasing GABA) and neurotrophic growth factors (increasing VEGF, BDNF, and GDNF), among others.

Cells as a whole act as mechanosensors

Although intensive research is under way to decipher the function of mechanotransduction and to identify novel cellular components involved in the detection and transduction of mechanical signals, it is important to understand that the cell as a whole essentially acts as a mechanosensor. The specific response to diverse mechanical stimuli is influenced by several factors, including cell type, cell shape, and the careful coordination of intricate dynamic signaling networks.

This cellular response mode can be essentially attributed to changes in the viscoelastic property of the cell. These are primarily based on the dynamic interactions of the central cytoskeletal components: Actin fibers, microtubules, and intermediate filaments. These three elements organize and cross-link each other using motor proteins and bonds, leading to the formation of structural complexes. These range from more rigid formations (such as rods) to more flexible structures (such as coils), giving the cell its specific mechanical characteristics.

Ultimately, the cell senses emergent forces, with the generated tension being transmitted through the cytoskeleton to the nucleus. There, mechanical stimuli are converted into changes in genetic activity patterns, which in turn stimulates specific cellular functions. This response results from the interaction of two complex and interrelated signaling pathways known as “mechanosensing” and “mechanotransduction.” Mechanosensing refers to the cell’s ability to detect changes in its mechanical environment. Mechanotransduction, on the other hand, encompasses the full range of molecular processes that convert extracellular forces into soluble biochemical signals. These signals stimulate specific cellular activities and include the processes by which cells generate cellular forces to modify the properties of their microenvironment. Both processes work together to integrate a wide range of mechanical signals both inside and outside the cell.

In their work, the researchers present a whole series of significant studies that help to clarify the intimate link between cellular homeostasis and the balance of mechanical properties of cells.

In summary, they highlight the relevance of studying homeostasis and dysfunction of cellular organelles for a deeper understanding of mechanotransduction processes. Although some overlap between the mechanisms of action of soluble signaling molecules and mechanical forces has already been deciphered, further research is needed.