Roles of Semaphorins in Neurodegenerative Diseases

Abstract

Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network. Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases. Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components. Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression. The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.

Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses

“…This resembles connective tissue disorder [73], including the skin barrier [74], occurring in MPS. Plexin-related changes have been connected to various impairments in functions of central nervous system [75][76][77][78] which are also common in some MPS types, as indicated in Figure 5C. Dysregulation of the MFGE8 gene has been linked to neurodegenerative processes dependent on the accumulation of amyloid [79][80][81][82], and a similar phenomenon has been described in MPS [83][84][85], which is presented in Figure 5D.…”

Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics

“…PRMT8 is an arginine methyltransferase that has been linked to stress tolerance in adult motor neurons ( Simandi et al, 2018 ). Finally, SEMA7A is expressed in both neurons and oligodendrocytes, and is involved in signaling to oligodendrocyte precursors in the case of neuronal injury, and in signaling to T-cells and protection against reactive oxygen species ( Quintremil et al, 2019 ). It is unclear why SEMA7A upregulation is seen in dementia-AD compared to resilient subjects, but it is striking that resilient subjects have the lowest SEMA7A levels of all four diagnostic groups ( Fig.…”

Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1

“…Given the importance of semaphorins in embryogenesis, their role in early embryonic development has been extensively studied. Their role in synaptic pruning and plasticity implicates these proteins in central nervous system (CNS) regeneration and potentially development of neurodegenerative disease 12,13 . It is known that semaphorins are involved with the homeostasis of the adult CNS and have been associated with the development of neurodegenerative disease 14 .…”

“…Their role in synaptic pruning and plasticity implicates these proteins in central nervous system (CNS) regeneration and potentially development of neurodegenerative disease. 12,13 It is known that semaphorins are involved with the homeostasis of the adult CNS and have been associated with the development of neurodegenerative disease. 14 For example, Sema3A has been linked with the development of Alzheimer's disease (AD) and is thought to prevent regeneration of injured neurons in the hippocampus via phosphorylation of intracellular collapsing response mediator protein-2 (CRMP-2), a protein that is associated with cytoskeletal integrity.…”