Musculoskeletal & Nervous System Biology

Agrin is a heparan sulfate proteoglycan secreted by the nerve terminal that binds to the receptor lipoprotein-related protein 4 (LRP4) to activate the muscle-specific kinase (MuSK) in the post-synaptic muscle membrane (1). This activation induces the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction, the site for signal transmission from a nerve to the muscle. Through these processes, agrin signaling promotes the formation and maintenance of the neuromuscular junction (2).

Dysregulated agrin signaling contributes to the pathogenesis of diseases associated with neuromuscular junction defects, including spinal muscular atrophy and congenital myasthenic syndrome. Understanding agrin's role at the neuromuscular junction is crucial for developing targeted therapies to treat these conditions and support healthy muscle function (3).

Axon (or axonal) guidance is a critical step in the development of the nervous system. For newly formed neurons to establish functional neural circuits, they must extend their axons toward their synaptic targets, a process called axon pathfinding (4). Axon guidance orchestrates axon pathfinding through attractive and repulsive extracellular molecular signals, including secreted factors, such as netrins, slits and semaphorins and cell adhesion molecules, such as cadherins and ephrins. Guidance receptors at the tips of moving axons encounter and interact with these signals, enabling axons to find their distant synaptic targets and form proper neural circuits (5).

Errors in axon guidance can contribute to the development of neurological disorders and developmental abnormalities, including horizontal gaze palsy with progressive scoliosis, congenital mirror movements and congenital fibrosis of the extraocular muscles, Type III (6). 

The gustatory pathway (or gustation pathway) is part of the brain circuit that determines whether food should be ingested for its nutritional value or rejected for potential toxicity based on its evaluation of food features, including taste, odor, texture, consistency and temperature (7).

The gustatory pathway begins with detecting a group of chemicals called tastants, including sugars, salts, acids, alkaloids and amino acids and culminates in the perception of taste in the brain. These tastants are linked to the five basic tastes: salty, sour, bitter, sweet and umami (savory). When consumed and mixed with saliva, the tastants  activate taste receptor cells in the taste buds, leading to the perception of the basic tastes. Information about the chemical identity of the tastant is carried via afferent fibers of three cranial nerves – the facial (cranial nerve VII), glossopharyngeal (cranial nerve IX) and vagus (cranial nerve X) – and then processed by brainstem nuclei before reaching the gustatory cortex, the part of the brain for perceiving and identifying different tastes. (8, 9)

Pathologies in taste perception, including the absence of taste, diminished taste, enhanced perception of taste and unpleasant perception of taste, may occur due to abnormalities such as abnormal saliva production, damage to taste buds, or damage to the cranial nerves associated with taste. These taste-related pathologies may also lead to more health problems like nutritional deficiencies, weight loss and reduced quality of life (10). 

Neuronal nitric oxide synthase (nNOS) is an isoform of nitric oxide synthase, an enzyme that catalyzes the synthesis of nitric oxide (NO)—a crucial signaling mediator for physiological processes—from of L-arginine (L-Arg). nNOS is expressed in nervous system cells and is strictly regulated by changes in intracellular Ca2+ levels mediated by the N-methyl-D-aspartate receptor (NMDAR) (11, 12).

The nNOS enzyme plays an important role in neuronal function and regulation as the principal source of NO. NO can be protective at lower concentrations, influencing synaptic plasticity, learning, memory and neurogenesis. However, at high concentrations, NO can be toxic to neurons, producing reactive species such as peroxynitrite and stable nitrosothiols and leading to irreversible cell damage associated with conditions such as Parkinson's and Alzheimer's disease (13). 

Neuronal nitric oxide synthase (nNOS) regulates various physiological events in skeletal muscles through its role in producing nitric oxide (NO). This secondary messenger mediates the activation of metabolic genes responsible for excitation-contraction coupling, muscle force generation, blood supply regulation, calcium homeostasis, myogenesis regulation, muscle repair and other processes associated with skeletal muscle cell function (14, 15).

Defective nNOS signaling is implicated in skeletal muscle diseases where muscle regeneration is impaired, including Duchenne muscular dystrophy, Becker muscular dystrophy, Ullrich congenital muscular dystrophy and inflammatory myositis.

Phototransduction involves the conversion of light energy absorbed by the photopigment rhodopsin in cells in the retina called photoreceptors into an electrical signal, resulting in the hyperpolarization of the photoreceptors and initiating vision (16).

Rhodopsin, a G protein-coupled receptor, consists of membrane protein opsin and a chromophore called 11-cis-retinal. In the absence of light, photoreceptors undergo depolarization due to the opening of ion channels by cyclic guanosine monophosphate (cGMP). When 11-cis-retinal absorbs light, it leads to rhodopsin activation which then results in cGMP decrease and the subsequent closure of ion channels, leading the cells to become hyperpolarized. As a result, neurotransmitter release decreases and retinal neurons detect the drop in neurotransmitters and carry the signal to the brain region, which is responsible for interpreting the signals into vision (17, 18).

Under physiological conditions, rhodopsin is only activated in response to light to initiate vision. Activation of rhodopsin without light can happen due to mutations or loss of 11-cis retinal and lead to retinal diseases such as Leber congenital amaurosis (LCA) and congenital night blindness (CNB) (19).

The visual cycle, also known as the retinoid cycle or chromophore recycling, is a vital biochemical process that occurs in the photoreceptors of vertebrate eyes. It exists to regenerate visual pigment after exposure to light, ensuring a constant supply of the necessary materials to capture light and maintain vision in a healthy eye (20).

The visual cycle relies on photoreceptor cells in the retina, the underlying retinal pigment epithelium (RPE) and the protein called RPE65 in the retinal pigment epithelium that lies next to the photoreceptor outer parts, to function. The process starts with the conversion of light energy into an electric signal in the retina via rhodopsin (21).

During the conversion of light into the electrical signal required for vision, the 11-cis-retinal converts through photoisomerization into all-trans-retinal, After all-trans-retinal is released from opsin, it is converted into a more stable form called all-trans-retinol, moved into neighboring retinal pigment epithelium and further processed into storage forms, like retinyl ester. When the eye needs more pigment, these stored forms are converted back to 11-cis-retinol and then 11-cis-retinal, which combines with opsin to form rhodopsin, ready to capture light again.

Disruptions in this cycle or defects in visual cycle proteins can lead to various visual impairments, including retinitis pigmentosa, Leber's congenital amaurosis and Stargardt's disease, highlighting its critical role in maintaining vision and overall eye health.

Bone modeling and remodeling are processes involved in bone formation and maintenance. They involve two types of bone cells: osteoclasts which remove old, mineralized bone and osteoblasts which create new bone matrix that then becomes mineralized (22).

 The combination of receptor activator of NF-κB (RANK), the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) regulates the formation, activation, maturation and survival of osteoclasts in bone modeling and remodeling (23). RANK/RANKL/OPG signaling helps maintain bone homeostasis, maintain bone strength and health, repair damage and regulate calcium levels in the body (24).

RANKL is a homotrimeric protein expressed by osteoblasts that binds to RANK, a receptor on the surface of osteoclasts. This interaction stimulates osteoclasts to mature and activate, increasing bone resorption. OPG secreted by osteoblasts, on their hand, binds to RANKL to prevent it from binding to RANK, inhibiting osteoclast differentiation, preventing excessive bone resorption and promoting bone formation (25).

Disruptions in this system can lead to bone diseases, including osteoporosis, rheumatoid arthritis, or periodontitis (26).