Kuru: The Dynamics of a Prion Disease

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Introduction

An elusive and unknown disease appeared in New Guinea in the early 1900’s. By the 1950’s anthropologists and government officials reported that this disease termed kuru was rampant among the South Fore. The South Fore were identified by Australian government officials in the 1950’s as a single census division consisting of approximately 8,000 individuals within the Okapa Subdistrict (Lindenbaum, 1979). Observe the following maps in order to see the exact location of the South Fore.

First Map

Second Map

This particular group was partaking in ritual acts of mortuary cannibalism, and this conduct was later held to be responsible for the transmission of the fatal kuru epidemic. This distinctive aspect of the illness made it even more fascinating to the various Western scholars who devoted their time to conquering it. Many efforts have been made to understand and describe kuru, and the knowledge of the dynamics of the disease has continued to grow, even though the disease all but disappeared in New Guinea with the termination of cannibalism. The pathology and symptoms of kuru are of specific interest here, as well as a comparison of kuru with other prion diseases. Scientists have now identified kuru as a prion disease. Understanding the structure and replication of the prion is crucial to interpreting the dynamics of kuru and several other prion diseases, which exist today. The onset of kuru led to a study of an unfamiliar disease that has lasted almost five decades. This particular disease serves as an example of the procedures scientists undergo in order to understand and appreciate all of the aspects of a disease and how potential therapies and solutions can be found.

Kuru Among the South Fore

Kuru is a neurodegenerative disorder that surfaced among the South Fore of New Guinea, and the dynamics of this disease have been explored by various scholars. Lindenbaum worked with the South Fore and studied the kuru disease. Zigas worked in New Guinea, and Gadjusek also traveled there in 1957 to study disease patterns in primitive and isolated populations (Gadjusek, 1996). Lindenbaum, Zigas, and Gadjusek were all crucial to explaining the marked, specific properties of kuru to the rest of the world.

The kuru epidemic reached its height in the 1960’s (Lindenbaum, 1979). Between 1957 and 1968, over 1,100 of the South Fore died from kuru (Lindenbaum, 1979). The vast majority of victims among the South Fore were women. In fact, eight times more women than men contracted the disease (Lindenbaum, 1979). It later affected small children and the elderly at a high rate as well. This is to be expected, since women were the prime participants in mortuary cannibalism (Lindenbaum, 1979). It is currently believed that kuru was transmitted among the South Fore through participation in such cannibalism. Upon the death of an individual, the maternal kin were in charge of the dismemberment of the corpse (Lindenbaum, 1979). The women would remove the arms and feet, strip the limbs of muscle, remove the brains, and cut open the chest in order to remove internal organs (Lindenbaum, 1979). Lindenbaum (1979) states that kuru victims were highly regarded as sources of food, because the layer of fat on victims who died quickly resembled pork. Women also were known to feed morsels such as human brains and various parts of organs to their children and the elderly (Lindenbaum, 1979).

Misinterpretations of Kuru

Scholars who first studied the disease among the South Fore initially had two major misconceptions concerning the nature of the disease. They first incorrectly postulated that it was a genetic disorder. After this possibility was ruled out, scientists next asserted that kuru was the manifestation of a slow virus. Genetic disorders can be fully understood through application to population genetics. Mutations provide variation and fuel natural selection. A genetic disorder is one that is caused by a mutation that is passed on to subsequent offspring. Since kuru had a tendency to occur among family members (Lindenbaum, 1979), the original notion that it was a genetic disorder seems somewhat appropriate. This possibility was eventually ruled out, because kuru was too common and too fatal (Lindenbaum, 1979). A completely lethal genetic disorder would drastically reduce the fitness of a population. Sooner or later it would die out of the gene pool. This fact led scholars to seek additional possible explanations to describe the dynamics of the disease.

Studies on chimpanzees injected with brain material from a victim led scientists to believe the agent was a slow virus, because the chimps developed a very similar condition after a long incubation period (Gadjusek et al., 1966). Gadjusek was responsible for conducting these tests on chimps. He defined a slow virus as a viral disease with an abnormally long incubation period (Gadjusek et al., 1966). In humans, kuru had an incubation period with a minimum of two years and maximum of 23 years (Lindenbaum, 1979:26). Gadjusek’s results also confirmed the infectious, transmittable nature of the prion. Mestel (1996:185) writes, "Since then, his [Gadjusek’s] team has shown that CJD [Creutzfeldt-Jakob disease] and GGS [German-Straussler-Scheinker syndrome] are also infectious..." With kuru, there was no evidence of an immune response or an antibody. It will become evident later that both of these hypotheses were incorrect. For now, the specific symptoms of kuru are relevant in gaining a more complete understanding of the disease as a neurological disorder.

Symptoms of Kuru

Gadjusek studied kuru, and he found the condition of kuru victims to be an upsetting sight. He explains, "...to see them, however, regularly progress to neurological degeneration in three to six months (usually three) and to death is another matter and cannot be shrugged off" (Gadjusek, 1996:10). Gadjusek (1973) reported three main stages in the progression of symptoms. The first stage is called the ambulant stage, and it includes unsteadiness of stance, gait, voice, hands, and eyes; deterioration of speech; tremor; shivering; in- coordination in lower extremities that moves slowly upward; and dysarthria (slurring of speech) (Gadjusek, 1973). The second stage is also known as the sedentary stage, and Gadjusek (1973) defines it with the following symptoms: patient can no longer walk without support, more severe tremors and ataxia (loss of coordination of the muscles), shock-like muscle jerks, emotional lability, outbursts of laughter, depression, and mental slowing (it is important to note that muscle degeneration has not occurred in this stage, and tendon reflexes are usually still normal) (Gadjusek, 1973). The third stage is the terminal stage, which is marked by the patient’s inability to sit up without support; more severe ataxia (loss of muscle coordination), tremor, and dysarthria (slurring of speech); urinary and faecal incontinence; difficulty swallowing (dysphagia); and deep ulcerations appear (Gadjusek, 1973). Cerebellar dysfunction is the cause of these conditions. Symptoms are generally common among prion diseases, as a comparison with Creutzfeldt-Jakob disease will demonstrate.

Comparison to CJD

Creutzfeldt-Jakob disease displays striking similarities to kuru in regards to symptoms displayed and organ damage (mostly to the brain). Comparisons and parallels are evident between these two prion diseases. By inspecting an in depth case study of CJD from Massachusetts General Hospital, it is possible to gain a more complete understanding of prion diseases.

At age 47, a woman feeling depression sought professional help at Massachusetts General Hospital (Scully et al., 1993). She became hypoactive, noticed impairment of her recent memory, and had urinary incontinence (Scully et al., 1993). Within a few months she became dizzy and had an unstable gait (Scully et al., 1993). At this point a computed tomographic scan (CAT scan) of the brain showed slight cerebral and central atrophy; delusion began to set in (Scully et al., 1993). According to Scully et al. (1993), by age 50 the patient’s cranial-nerve functions were still normal, as well as motor power, sensation, and coordination. The next symptom to appear was the occurrence of inappropriate laughter, and her replies to questions became irrelevant and incorrect (Scully et al., 1993). Mild tremor was noted, although the cranial-nerve functions, strength, coordination, and sensation were still intact (Scully et al., 1993). At this time another CAT scan was performed, and the results were the same as the year before (Scully et al., 1993). Within a week after this scan, she was readmitted with shaking spells (Scully et al., 1993). There was a constant alteration between laughing and crying, but reflexes were still normal (Scully et al., 1993). By the age of 51 and a half years, her speech had deteriorated rapidly, and a new CAT scan showed marked cerebral and cerebellar atrophy (Scully et al., 1993). According to Scully et al. (1993), gradual deterioration continued up until her death four months prior to her fifty-fourth birthday.

Important similarities occur between Creutzfeldt-Jakob disease (CJD) and kuru. Both prion diseases cause tremor and inappropriate laughter. Depression was expressed early in CJD and in stage two of kuru. Unsteadiness in gait and sporadic muscle jerks were observed in both ailments. Dysarthria occurred in kuru during the initial stages of the diseases and in CJD more towards the end, and the exact same situation is seen with the condition of urinary incontinence as well.

The Prion Protein

The exact nature of kuru perplexed scholars for decades after the discovery of the ailment, until Prusiner identified and defined prion diseases in 1982 (Prusiner, 1995). Prusiner (1991) classified a prion as an infectious particle composed of a protein that causes neurodegenerative disorders. According to Cashman (1997), prions are infectious agents by biological and medical criteria. However, they are also fairly unique, and properties of prions differ from those of conventional microbes. All known prion diseases are fatal. Such diseases are often called spongiform encephalies, because they frequently cause the brain to become spongy and riddled with holes (Prusiner, 1995). Well known prion diseases include scrapie, bovine spongiform encephalopathy (mad cow disease or BSE), and Creutzfeldt-Jakob disease (CJD). Less well-known prion diseases include the following: transmissible mink encephalopathy, chronic wasting disease, feline spongiform encephalopathy, exotic ungulate encephalopathy, German-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (Krakauer et al., 1997). Of these infirmities, four affect humans: Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru. The most common form of prion disease is scrapie, expressed in sheep and goats (Prusiner, 1995). According to Cohen et al. (1994), prions cause a variety of degenerative neurologic diseases that can be infectious, inherited, or sporadic in origin. The cause of the sporadic forms is unknown; inherited forms are caused by up to twenty different mutations of the human PrP gene; and the infectious forms are transmitted through contact with or consumption of previously infected tissues (Prusiner, 1997).

PrPC is the normal, cellular prion protein, and it is converted into PrPSc (Prusiner, 1997). Mutations in the 102nd codon of this gene have been linked to neurodegeneration, which is the main, encompassing attribute of the prion diseases. Prusiner (1995) identified 15 amino acids at one end of the PrP protein. Using this knowledge, molecular probes were constructed and used to study the sequences of the normal verses the mutated form of the gene (Prusiner, 1995). Specifically, Prusiner discovered that the amino acid leucine is substituted by the amino acid proline (Prusiner, 1995). An incident of this type is commonly known as a point mutation. In the case of prion proteins, this mutation encodes additional copies of an octapeptide repeat toward the 5' end (Krakauer et al., 1997). The normal protein consists of mainly alpha helices with a spiral backbone, but the new, mutated prion protein is predominately formed by beta strands with a fully extended backbone (Prusiner, 1995). This alteration in tertiary structure provides evidence for post-translational modification of the protein. Observe the following illustration in order to see the tertiary structure of PrPSc:

FIGURE 1

It is essential to gain a more detailed understanding of the prion protein’s specific structure in order to comprehend kuru and other similar maladies.

Structure of a Prion Protein

The structure of a prion protein and its replication are fundamental to studying kuru. Although the precise details concerning the configuration of the prion were initially unclear, Prusiner was able to put forth three hypotheses. He claimed:

Hypotheses for the structure of the infectious prion particle included the following: (i) proteins surrounding a nucleic acid that encodes the proteins (a virus), (ii) proteins associated with a small polynucleotide, and (iii) proteins devoid of nucleic acid (Prusiner, 1991:1515).

Subsequent to the publication of this article, thousands of scientists tried to figure out the prion puzzle. According to Prusiner (1995), extracts from scrapie-infected brains were subjected to ultraviolet and ioninzing radiation (Prusiner, 1995). Such treatments usually destroy nucleic acids, but these tissues remained infectious (Prusiner, 1995). Prusiner (1995) concluded that the scrapie agent was indeed nucleotide-free, like a protein. This means that a prion does not contain DNA or RNA, which disproved Prusiner’s first hypothesis (that the prion could possibly be a virus). Furthermore, the prion was inactivated by extreme treatments that destroy or denature proteins, such as chaotropic ions or denaturing detergents (Cashman, 1997). After discovering these clues, scientists began to question the prion’s method of replication.

Cashman (1997) has suggested that the same nucleic acid and amino acid sequence gave rise to the two, different proteins. Further studies indicated the structural differences between the normal protein PrPC and the abnormal prion protein PrPSc. To summarize, the normal protein (PrPC) dissolves in nondenaturing detergents and breaks down easily with exposure to proteases, but PrPSc does not dissolve and is partially resistant to proteases (Prusiner, 1997). PrPSc can inhabit various acidic or basic environments, because it is stable between pH 2 and 10 and has survived two year immersions in formol saline (Mims and White, 1984). The last important feature to note with respect to the pathogenic prion particle is that the prion protein gene (PrP) in laboratory mice controlled the incubation time, neuropathology, and prion synthesis within the infected organism (Prusiner 1991).

Prion Replication

Scientists believe that the replication of a prion particle occurs almost exactly as the duplication of a virus. The mechanism of replication involves the synthesis of polypeptides in the absence of nucleic acid templates and the post-translational modifications of cellular proteins (Prusiner, 1991). A polypeptide is a chain of amino acids, and a nucleic acid template is a group of DNA or RNA molecules that carry information to direct cellular functions. For the prion, replication involves converting conventional proteins into prions. The resulting PrPSc is a four helix bundle protein with four regions of secondary structure, numbered H1 through H4 (Prusiner, 1997). Mestel (1996) explains that prions replicate by recruiting normal proteins to their cause, "flipping" them into a rogue prion-like shape that can go on to infect other cells and animals. This change initiates a chain reaction, and newly converted prions convert other proteins which they come into contact with on the interior of their respective cell membrane (Prusiner, 1995). In cell cultures, the conversion occurred inside neurons. The PrPSc accumulated in lysosomes and eventually filled the lysosomes until they exploded, releasing the prions to attack other cells (Prusiner, 1995). Future understanding of the operation of the PrP gene could possibly lead to a manipulation of these conditions in patients with a prion disease.

Development of Therapies

Currently, Prusiner (1995) believes that a more comprehensive understanding of the three-dimensional structure of the PrP protein will lead to the development of therapies. According to Prusiner (1995), experiments with laboratory mice were conducted. The PrP gene was targeted, and mice lacking the gene were created (Prusiner, 1995). In this case, the animals did not display any noticeable side effects or abnormalities (Prusiner, 1995). This is encouraging: if further studies show the PrP gene to be inessential, then physicians may be able to inject antigene therapies to patients with prion diseases in the future (Prusiner, 1995).

Recently, prion infections have been termed amyloidoses (Serpell et al., 1997). Serpell and colleagues state, "Amyloidoses are diseases...in which soluble proteins are deposited in a specific, highly stable, fibrillar form" (Serpell et al., 1997:871). Amyloid fibrils have three diagnostic characteristics: under the electron microscope, the fibrils are straight and unbranched with a smooth surface; amyloid fibrils can be stained with Congo Red and subsequently exhibit an apple-green birefringe; and they have a distinct X-ray defraction pattern, indicative of the beta sheets found in the PrPSc formation (Serpell et al., 1997). The following picture illustrates the hydrogen bonding patterns in beta-sheet structure:

FIGURE 2

Understanding the process of amyloid formation may aid in the development of therapies for such diseases.

Since the 1950s, scientists have worked on the prion puzzle. Microbiologists and epidemiologists have been confused by the prions. Advancements have been made, especially in the 1990s. This can be evidenced by Prusiner's reception of the Nobel Prize in 1997. However, it has still been difficult to detect prion infection, track its transmission, and type the different strains (Cashman, 1997). The Fore experienced a long struggle with kuru, which serves as a poignant example.

Conclusion

Since the discovery of the kuru epidemic in New Guinea, a vast amount of knowledge has been gained concerning prion diseases. The specific dynamics of the kuru disease are important to realize in order to better understand all prion diseases. Scientists admit that there is still a lot of ground to cover in this area of research. Numerous questions have been answered, yet many puzzles still remain to be solved. A large amount of the work done in the name of understanding prion diseases was carried out by anthropologists in the field studying the Fore. Their contributions to this research have played an enormous role. Fortunately, kuru has disappeared in New Guinea, but many prion diseases remain that can attack humans and animals. Although the case may be closed for kuru, the other prion diseases must continue to be studied in the hopes of conquering these illnesses.

References Cited

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