Cellular response to stress
Cellular stress can be defined as a state in which the cell does not have optimal survival conditions. Extreme temperatures, toxins, lack of oxygen, oxidative injury, or mechanical shock are some examples of stressors that can harm cells. As a result, they go through a series of chemical changes known as the cellular stress response. The response to stress especially affects gene expression, that is, the repertoire of proteins present in cells and that will be responsible for giving an adequate response to mitigate the harmful effects of stress and promote cell adaptation to the new environmental situation.
The manner that cells react to stress varies, from activating pathways that aid in survival to causing programmed cell death, which kills off damaged cells. This reaction’s great evolutionary conservation may be explained by the fact that a cell’s capacity to establish a suitable defense against external or internal stressors is essential to its ability to survive.
Stressors that have evolved as a component of host defense in mammals include abrupt temperature changes during host invasion and/or inflammation, abrupt pH drops when ingested bacteria pass through the mammalian stomach, and exposure to extremely high levels of reactive oxygen species during macrophage (specialized cells that detect and destroy bacteria and other harmful organisms) oxidative burst.
In a matter of seconds or minutes, each of these stressors significantly damages cells while simultaneously changing the stability, structure, and function of a wide range of proteins. This stress plays an important role in the occurrence of both cellular senescence and some diseases. However, to resist these sudden onset protein-damaging conditions, organisms have created a subclass of proteins called “chaperones” that stop other proteins from clumping together and becoming entangled. These chaperones are activated under very specific stress conditions and protect the cells from cellular damage.
Other cellular protection mechanisms include the heat shock response. When a cell, tissue, or entire organism is subjected to high temperatures, the heat shock response is defined by the fast expression of a class of proteins known as heat shock proteins, which improves the cell’s ability to fold proteins, reducing the effects of stress and improving cell survival.
Heat shock proteins can also be found in non-stressful conditions, simply “monitoring” the proteins in the cell. Their role as “monitors” includes transporting old proteins to the cell’s “recycling bin” (proteasome) and assisting newly synthesized proteins in folding properly. These activities are part of the “cellular stress response” or “heat shock response,” which is a cell’s own repair system.
The importance of garbage recycling
A gene is the most fundamental physical and functional unit of heredity. DNA (deoxyribonucleic acid) is the building block of genes. Some genes serve as building plans for the creation of proteins. However, not all genes code for proteins. Genes in humans range in size from a few hundred DNA bases to over 2 million bases. The Human Genome Project, an international research effort that sequenced the human genome and identified its genes, estimated that humans have between 25,000 and 30,000 genes. Capable of producing approximately 42 million protein molecules per cell.
Proteins are large, complex molecules that carry out numerous important functions in the body. They serve a variety of functions in cells and are required for the structure, function, and regulation of body tissues and organs. Whatever function they serve, they are always linked to another molecule, whether that molecule is DNA, RNA, lipids, sugars, or another protein.
Ubiquitin is a tiny protein in all body cells and regulates several processes, including protein degradation, cell growth control, DNA repair, neuron development, muscular degeneration, and stress response. When researchers discovered ubiquitin, they discovered that proteins that link to ubiquitin or are ubiquitinated are designated for elimination. The researchers who made this discovery in 1980 received The Nobel Prize (2004) in Chemistry. This discovery provided the first explanation for how old proteins are recycled and new ones are generated.
The ubiquitin, whose name comes from the Latin ubīque (which means “everywhere”) has been crucial in understanding how critical it is for the body to eliminate cellular waste. In actuality, the effects of this system’s malfunction do not go unnoticed. Changes in the breakdown of proteins and organelles have a significant impact on the ability of cells to divide, and as a result, are frequently linked to the development of a wide range of diseases, including cancer, amyotrophic lateral sclerosis, and several neurological diseases such as Alzheimer’s, Parkinson’s, neuronal degeneration, transmissible spongiform encephalopathies, and Huntington’s disease.
The ubiquitination system is composed of three enzymes: E1 (deactivation), E2 (conjugation), and E3 (ligation). The E2 enzyme interacts with E1 and E3 and is a crucial transfer point for ubiquitination. The Rad6 gene, which encodes the ubiquitin-conjugating enzyme (E2), is highly conserved across organisms and was discovered for the first time in the bread yeast Saccharomyces cerevisiae. However, the removal of one or more nucleotides from a DNA segment (known as deletion) of the E2 Rad6 gene impacts ubiquitin chain accumulation under cell stress conditions.
Homology describes the descent of two genes from a common evolutionary origin: two genes are homologous if they are descended from the same ancestral gene. In humans, the UBE2A was discovered to be the human homolog of the Rad6 gene.
The UBE2A gene encodes a ubiquitin-conjugating enzyme to ubiquitinate mitochondrial proteins and facilitates the proper elimination of dysfunctional mitochondria which are the cellular organelles that generate the majority of the chemical energy required to activate the cell’s biochemical reactions.
A recent publication on May 24 in the journal Cell Reports discovered that mutations in the human homolog of Rad6(UBE2A) have been associated with cognitive and learning deficits and in humans have led to the intellectual disability type Nascimento. Mitochondrial dysfunction caused by UBE2A mutations may result in synaptic transmission defects and an accumulation of modified, potentially toxic proteins in neurons, which can result in neuronal injury or premature neuronal death.
X-linked intellectual disability (XLID) is a medical syndrome associated with sex-linked heredity. Although the X chromosome makes up just around 5% of the human genome, it contains 15% of the genes that are currently known to be linked to intellectual impairment. As a result, the X-chromosome was chosen for the study due to the high proportion of males among people with intellectual disabilities (XLID) and the availability of numerous families in which ID followed an X-linked pattern of inheritance.
Chromosomes are the structures in the nucleus of the cell that carries the genetic information of each individual. Chromosomes are composed of chromatin, which is composed of histones (structural proteins) and DNA (deoxyribonucleic acid). The normal diploid number of chromosomes in humans is 46, distributed in 22 autosomal pairs and one pair of sex chromosomes.
Certain disorders (including some forms of color blindness, hemophilia, and muscular dystrophy) are X-linked in humans. Biological sex in humans and other mammals is determined by a pair of sex chromosomes: XY in males and XX in females. X-linked genes are those that are found on the X chromosome. Because there are differing numbers of X-linked genes in males (XY) and females (XX), they have different inheritance patterns.
Females who are heterozygous (have two different alleles) for disease alleles are known as carriers, and they typically do not exhibit symptoms. Sons of these females have a 50% chance of having the disorder, but daughters have a low chance of having it (unless the father also has it) and instead have a 50% chance of being carriers (Figure 1). Males are more likely than females to have X-linked recessive traits because if a male receives a “bad”allele from his mother, he has no chance of receiving a “good” allele from his father, who provides a Y chromosome to hide the bad gene. Females, on the other hand, are more likely to inherit a normal allele from their father, preventing the disease allele from being expressed. Therefore, the biological inequity between males and females conferred by the presence of a single X chromosome in males has been thought to be primarily responsible for such a significant gender bias, implying that genes on the X chromosome play a primary role in the causation of XLID.
Figure 1. Intellectual disability linked to X (XLID) has been associated with mutations in the UBE2A Arg7 gene. Genetic defects on the X chromosome are thought to play a significant role in this gender bias. The disease is less frequent in women since having two copies (one for each sex chromosome) of the gene can mask the deleterious effects of the mutations.
Credit: Francisco J. Balvino-Olvera
X-linked intellectual disability type Nascimento
Over 150 syndromes have been described in humans, the most common of which is the fragile X syndrome and intellectual disability type Nascimento. X-linked syndromic intellectual disability Nascimento was first described as a distinct entity in 2006 by Nascimento and colleagues, who discovered a nonsense mutation in UBE2A in three intellectually disabled males from a two-generation family. X-linked intellectual disability (XLID) type Nascimento is a relatively common disorder with a prevalence of 2-3% of the global population and is characterized by significant limitations in both intellectual functioning and adaptive behavior.
Intellectual disability, defined as a significant impairment of cognitive and adaptive functions, is a multifaceted human phenomenon. It represents a cloak for the affected individual, limiting their ability to learn, plan, solve problems, think abstractly, understand complicated ideas, learn fast, and learn from experience, and reducing social, and practical abilities that humans learn and use on a daily basis. As with most X-linked disorders, males are more heavily affected than females.
There are two types of X-linked intellectual disability: syndromal and non-syndromal (or nonspecific). Physical, neurologic, behavioral, or metabolic abnormalities frequently accompany syndromal X-linked intellectual disability and form a recognizable pattern. Males with non-syndromal X-linked intellectual disability have no physical, neurologic, behavioral, or metabolic differences from nonaffected brothers or other males with intellectual disability. X-linked disorders are a common abnormality in public health, affecting all strata of the population and imposing a costly and lifelong burden. For society, it is a disability marked by decreased productivity, some degree of dependency, and vulnerability to discrimination and exploitation.
Prognosis and treatment availability
XLID can be diagnosed by testing a person’s DNA from a blood test. The test can be ordered by a doctor or a genetic counselor. Changes in the UBE2A gene that can cause X- linked disorders can also be tested. A diagnosis of XLID can help a family understand why their child has intellectual disabilities and behavioral issues. This enables the family and other caregivers to gain a better understanding of the disorder and manage care so that the child can reach his or her full potential.
Although more than 140 XLID genes have been identified in humans, the molecular and developmental mechanisms underlying this disorder remain mostly unknown. Nascimento syndrome has no known cure. However, molecular testing is becoming increasingly affordable. This will allow for the addition of pre-pregnancy testing for carriers of X-linked ID to routine screenings.
Treatment services, on the other hand, can assist people in learning important skills. Therapy to learn to talk, walk, and interact with others is one example of a service. Furthermore, medicine can be used to help control some issues, such as behavioral issues. People with Nascimento syndrome, their parents, and medical personnel should work closely together to develop the best treatment plan possible.
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