Biochemical Pathways of Cellular Mechanosensing/Mechanotransduction and Their Role in Neurodegenerative Diseases Pathogenesis

Abstract

In this review, we shed light on recent advances regarding the characterization of biochemical pathways of cellular mechanosensing and mechanotransduction with particular attention to their role in neurodegenerative disease pathogenesis. While the mechanistic components of these pathways are mostly uncovered today, the crosstalk between mechanical forces and soluble intracellular signaling is still not fully elucidated. Here, we recapitulate the general concepts of mechanobiology and the mechanisms that govern the mechanosensing and mechanotransduction processes, and we examine the crosstalk between mechanical stimuli and intracellular biochemical response, highlighting their effect on cellular organelles’ homeostasis and dysfunction. In particular, we discuss the current knowledge about the translation of mechanosignaling into biochemical signaling, focusing on those diseases that encompass metabolic accumulation of mutant proteins and have as primary characteristics the formation of pathological intracellular aggregates, such as Alzheimer’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis and Parkinson’s Disease. Overall, recent findings elucidate how mechanosensing and mechanotransduction pathways may be crucial to understand the pathogenic mechanisms underlying neurodegenerative diseases and emphasize the importance of these pathways for identifying potential therapeutic targets.

Tight Regulation of Mechanotransducer Proteins Distinguishes the Response of Adult Multipotent Mesenchymal Cells on PBCE-Derivative Polymer Films with Different Hydrophilicity and Stiffness

“…Mechanical forces are now acknowledged as a crucial regulator of lifeforms and functions in all aspects of biology [ 1 , 2 ] due to the capability of cells to be sensitive to physical stimuli of different magnitudes at micro- or nanoscale levels and to convert them into biochemical responses [ 1 , 2 , 3 ]. These molecular pathways, known as mechanosensing and mechanotransduction, are critical for cellular physiology, tissue development, and the maintenance of cell homeostasis and function [ 4 , 5 , 6 , 7 , 8 ]. Both processes involve specific classes of “mechanosensor” proteins that sense external mechanical forces (mechanosensing) and respond by activating intracellular signal pathways (mechanotransduction), resulting in gene expression regulation and, in turn, the control of cellular function(s) [ 1 , 2 ].…”

Novel Nanostructured Scaffolds of Poly(butylene trans-1,4-cyclohexanedicarboxylate)-Based Copolymers with Tailored Hydrophilicity and Stiffness: Implication for Tissue Engineering Modeling

“…These scaffolds must satisfy specific requirements in terms of mechanical properties (e.g., elasticity, stiffness), surface properties (hydrophilicity, micro-/nano-topography, roughness/smoothness), and other chemical–physical characteristics, altogether recapitulating the tissue that must be regenerated. Among these, mechanical properties might influence cell morphology [ 1 , 2 , 3 , 4 , 5 ], surface hydrophilicity, and cell adhesion and proliferation [ 5 ]. Therefore, the appropriate modulation of these properties should have a great impact on cell fate.…”

The Cytoskeleton and Its Binding Proteins as Mechanosensors, Transducers, and Functional Regulators of Cells

“…Moreover, cytoskeleton-binding proteins (CBPs) orchestrate these functions by interacting with cytoskeletal components to form a complex system key to generating cellular biochemical responses to physical and mechanical stimuli through mechanosensing and mechanotransduction [ 4 , 5 ]. Therefore, the dysregulation of these interactions can lead to numerous diseases, such as malignancies, degenerative disorders, and metabolic diseases [ 6 , 7 , 8 ].…”