Progeria? - Literature - Cellular Mechanisms of Progeria
 

Cellular Mechanisms of Progeria
Biol. 2402 - Anatomy & Physiology
Richland College, Spring 2001 Class Project
Web Project Members: Ami Stovall, Amanda Dean, Helen Chen

Diseases in humans generally arrive from one of two sources:
- external agents
- defects already present in the organism

One of the major theories of aging is that it results from the inability either to:
- read
- repair
- or replicate DNA

(Telomeres keep the DNA strand from unraveling [DO NOT code for traits], and Helicases are not directly involved in any of these functions, but they prepare the DNA for all of the above (Human Genetic Diseases That Mimic the Aging Process, p. 1 & 8).

Progeroid syndromes are rare genetic disorders that accelerate the aging process causing multiple effects on the body. The two main syndromes, Werner’s syndrome and Hutchinson-Gilford syndrome differ in the age of onset. Werner’s syndrome generally doesn’t appear until the second to third decade of life whereas the Hutchinson-Gilford syndrome is evident within the first five to ten years of life. There are many facets to these diseases including genetics, symptoms, treatment and how these disorders affect the body. In order to gain a better understanding of such conditions as Werner’s syndrome and Hutchinson-Gilford syndrome, one must consider what is happening at the cellular level. This leads to theories of possible causes of these disorders which includes:

- mutant gene theory
- telomere theory
- free radical theory
- helicase theory

Before proceeding, here are some helpful definitions to better understand the text:
- Germ cells - sperm (spermatozoa) or eggs (ova); cells who function is to reproduce the organism; haploid - single set of chromosomes
- Stem cells - undifferentiated cells that can differentiate into functioning body cells; a cell capable of both differentiation and self-renewal
- Somatic cells - differentiated functioning body cells; have two sets of chromosomes, diploid and are represented by cells of many shapes and functions
- Hayflick’s limit - the number of cell divisions that will take place in human cell cultures prior to dying out; this is estimated to be about 50 cell divisions. Dr. Hayflick estimated that the limit of life of human beings could be more than 100 years.
- Senescence - the process of growing old; the period of old age
- Helicase - is an enzyme that untwists the double helix at the replication fork, separating the two old strands (unwind the parental double helix)
- Telomere - the protective structure at each end of a eukaryotic chromosome. Specifically, the tandemly repetitive DNA at the end of the chromosome’s DNA molecule
- Telomerase - an enzyme that catalyzes the lengthening of telomeres; the enzyme includes a molecule of RNA that serves as a template for new telomere segments

Normal Functions of Telomeres (TTAGGGTTAGGGTTAGGG…)
Before learning the pathology of progeria, it’s a good idea to start with the normal cellular mechanism of aging. Comprehending the normal function of telomeres is a critical part in understanding progeria. It plays an important role in cellular aging. The repeating DNA sequences at the end of chromosomes are called telomeres. Their main function in the human body is to maintain the base pair sequence on the tips of the chromosomes. Preventing chromosomes from fusing to each other is another function of telomeres. Telomere shortening over the life span is a process of normal aging. In normal cells, some telomere is lost each time the cell divides and grows. After many cell divisions, the chromosome reaches a “critical length” and can no-longer replicate. Eventually the aged cell dies. This cellular aging process of shortening of the telomeres may be one of the most important determinants of human life span.

The Role of Telomeres in Progeroid Syndromes
Currently in the aging process, the role of telomeres hasn’t been fully established. At the end of a linear chromosome, these repetitive DNA sequences avoid DNA polymerase’s (an enzyme that catalyzes the elongation of a new DNA at a replication fork during DNA replication) inability to completely replicate the end of chromosomes. “In progeria cells, telomeres are short and prevent further replication at a critically reduced length. This allows DNA damage to occur unrepaired” (Dyer and Sinclair). “Genetically defective (shorter) telomeres could allow for cells that age, and die, drastically faster than in the average healthy person.

As a result, this leads to the eventual variety of symptoms associated with progeria. For an excellent movie regarding telomeres and their processes in aging and to obtain a better general idea of their roles go to: http://centre.edu/`bmb/movies/Telomeres.html .

Keeping DNA strands from unraveling, telomeres don’t code for any traits. The daughter cell produced when a cell divides has a little less telomere at the end to work with. Further cell divisions and reaching it’s Hayflick limit of about 50 cell divisions, it is much shorter and when the cell stops replicating, the genes that were covered by the previously longer telomeres become exposed and active, which produced proteins that triggered deterioration of tissues associated with the aging process. It was found that sperm cells and cancer cells unlike most cells in the body, exhibit telomere loss.

“Research was done to explore those cells that were spared of the telomere loss. Telomerase (the telomere-preserving enzyme) was found in the precursor cells that give rise to:
- human eggs
- stem cells that give rise to blood cells
- up to 95% of cancer cells

Through research, it was determined that telomerase keeps cells such as these going, preserving telomeres in the process. Further research is being done to look for the gene(s) that direct telomerase production. Through this process though, of concern is the fact that dosing cells with telomerase is to be considered unsafe currently due to this enzyme thus helps healthy cells turn cancerous. Locating the gene(s)is at present, the challenge considering that there are approximately 100,000 or so genes in each cell. Eventually, they are exploring manipulating this enzyme (telomerase) to help cells and the body to lengthen their programmed life span.

Learning more about telomeres and telomerases that preserve telomeres and thus the length of chromosomes during the replication process and eventually lengthening life span would further contribute to figuring out how to attack diseases such as progeria and therefore preventing this premature aging process and it’s devastating effects on humans.

Of note in regards to telomeres and progeria:
- Werner’s syndrome - one form of progeria in which a symptom present is cancer
- Hutchinson-Gilford - another form in which the symptom of cancer is absent

Normal Functions of Helicase
To gain a better understanding of the possible role helicase plays in aging as well as in progeria, one should have a grasp of DNA replication and the normal functioning role helicase has in this process.

First, deoxyribonucleic acid (DNA) is a complex nucleic acid of high molecular weight consisting of deoxyribose, phosophoric acid, and four bases (two purines, adenine and guanine, and two pyrimidines, thymine and cytosine). These are arranged as tow long chains that twist around each other to form a double helix joined by bonds between the complementary complements. Nucleic acid, present in chromosomes of the nuclei of cells, is the chemical basis of heredity and the carrier of genetic information for all organisms…”

In the process of DNA replication, the parental DNA molecule serving as a template makes an exact copy of itself. “This replication of an enormous amount of information is achieved with very few errors - only about one per billion nucleotides”. DNA replication occurs with remarkable speed and accuracy. Many enzymes and proteins are involved in this process including:
- Helicase - an enzyme that begins the process by unwinding the DNA double helix
- Binding proteins - on the single-stranded DNA function to stabilize the unwound DNA
- DNA polymerase - in the leading strand, it catalyzes the elongation, & continuous synthesis of the leading strand, in addition to replacing of DNA with RNA primer, and in the lagging strand, it functions in the extension of RNA primer to form a series of pieces called Okasaki Fragments
- Primase - functions in the synthesis of an RNA primer
- DNA ligase - is then required to join the Okasaki Fragments into a single DNA strand
- Helicase is important in the DNA replication because it prepares it for replication by unwinding the complex molecule. As a result, any malfunction with this enzyme would have devastating consequences. In regards to the theories of aging and progeria, any malfunctions in the processes of reading, repairing, or replicating DNA for which helicase among others are involved results in the devastating manifestations of such diseases as progeria.

Helicase in Progeroid Syndromes
The difference between normal human chromosomes and those in patients with progeroid syndromes, such as Werner’s syndrome or Hutchinson-Gilford, are numerous. There have been links found in the DNA of the chromosomes and the enzymes involved. Though many of them remain to be clarified, the implication that DNA helicases have a role in chromosomal stability and the lack thereof, has been studied as a possible link to progeroid syndromes.

DNA helicases have been known to play a role in many molecular processes. Mainly, this enzyme is responsible for unwinding the DNA during replication, DNA repair, and separation of the chromosomes. Basically, they pry apart the two strands of the double helix.

In Werner’s syndrome, gene mutations suggest that somehow helicase is disrupted. Though the mutations themselves are a possible cause of the disease, some of the mutations studied showed a defect in the helicase domain region, or an absence of the region altogether. This causes a chromosome to “malfunction” and not work properly.

It was also suggested that the helicase defective in Werner’s syndrome is missing, a signal called the nuclear localization signal (NLS). This is a potential factor contributing to molecular inactivity in this disorder.

Though the definitive causes of progeroid syndromes remain to be found, it is known that the DNA in these syndromes is different from those in normal humans. The proteins and enzymes that play such a vital role in our chromosomes are somehow defective, leading to potential disorders, such as Werner’s syndrome, or Hutchinson-Gilford.

In conclusion, there are several theories in progeroid syndromes. The main theories detail the cellular mechanisms in regards to the genetic makeup of a cell and possible malfunctions, which in turn produce such symptoms of these diseases. Although a definitive cause has not yet been identified, we do know that if such alterations as those discussed in this website occur, there is a direct correlation to the symptomology of Werner’s syndrome and Hutchinson-Gilford syndrome.

Click image to view larger version
This image shows the part of the chromosome (chromosome 8) that codes for Werner's Syndrome