INTRODUCTION

1.1 Definition of Proteasomes Proteasomes are considered to be one of organelles in our cell. These are protein degradative machines that are found in the nucleus and the cytoplasm. They are not only found in all eukaryotic organisms, but have also been found in archaebacteria. Complex that degrades protein is usually called 26S-Proteasome or only proteasome. Proteasomes play many roles in the cell's life, those are: 1. They remove abnormal and misfolded proteins from the cell. 2. They are involved in the cell's stress response, where they degrade Ubconjugated regulatory proteins. 3. As part of the Ub system, they are involved in regulating the cell cycle. 4. They are involved in cellular differentiation (where they degrade transcription factors and metabolic enzymes). 5. They play an important role in the immune system by generating antigenic peptides that are presented by the major histocompatibility complex (MHC) class I molecules (such molecules are studied in Immunology). In short, proteasome activity is involved in most of the processes that also involve ubiquitin. We know they are essential because the removal of proteasome genes in eukaryotes is lethal. Proteasomes are cylindrical structures. Like all cellular machines, proteasomes use ATP to drive conformational changes in their subunits. ATP hydrolysis is not needed to actually cleave the peptide bonds of a protein, but instead is thought to involve recognition of target proteins, their unfolding, the translocation of the substrate protein into the proteasome's chamber, and/or the opening and closing of proteasome gates. Proteasomes deal primarily with endogenous proteins; that is, proteins that were synthesized within the cell such as transcription factors, cyclins (which must be destroyed to prepare for the next step in the cell cycle), proteins encoded by viruses and other intracellular pathogens, proteins that are folded incorrectly because of translation errors.

1.2 Structure of Proteasomes The 26S proteasome is a multiprotein complex consisting of a 20S core particle that is associated with one or 2 19S regulatory particles (Figure 1). Each 19S subunit is capable of binding the polyubiquitin chain and cleaving it from the protein substrate. The substrate is then denatured, or unfolded, and fed into the proteolytic core. The 20S core particle is a cylinder composed of 4 stacked rings and has little relevant proteolytic activity in its cellular milieu. The 2 outer rings (called a rings) complex with the 19S regulatory particles, forming a narrow

Figure 1 Proteasomes structure channel through which only denatured proteins may pass. The catalytic chamber is formed by the 2 inner b rings, each of which contains 3 active sites. These sites differ in their substrate specificity and activity and have been named after enzymes that show similar proteolytic activity or specificity. These active sites are thus termed chymotrypsin-like, trypsin-like, and post-glutamyl peptide hydrolaselike (PGPH). Proteins are degraded by the core particle in a progressive manner, generating peptides of 325 amino acids in length. .

1.3 The UbiquitinProteasome System (UPS) For a protein to be recognized by the proteasome, a small peptide (ubiquitin) must first be attached to the target protein. This process is carried out by a cascade of enzymes (Figure 2) that activate free ubiquitin and carry it to the target protein. These enzymes are called E1, E2, and E3. E1 activates and transfers ubiquitin to the carrier protein E2. E2 presents ubiquitin to E3. E3 binds to the target protein and interacts with E2 to covalently attach ubiquitin to the target protein. This process is carried out several times, creating a polyubiquitin chain that flags the protein for destruction by the proteasome.

Figure 2 The ubiquitin-proteasome pathway. Proteins marked with a polyubiquitin chain by the E1-E2-E3 enzymatic cascade are targeted for degradation by the proteasome. A ubiquitin-activating enzyme (E1) binds ubiquitin in an adenosine triphosphate (ATP) dependent step. Ubiquitin is then transferred to a ubiquitin-conjugating enzyme (E2). A ubiquitin ligase (E3) helps transfer ubiquitin to the target substrate. PPI, pyrophosphate; AMP, adenosine monophosphate; Ub, ubiquitin. (Figure and legend adapted30 and used by permission from Elsevier.) To date, only one known E1 enzyme exists, but about 20 E2 enzymes have been identified in yeast and humans, and an even larger number (perhaps hundreds) of E3 ligases exist. This hierarchical structure (i.e., a limited number of E2s and a larger number of E3s with limited substrate specificity) allows for highly specific interactions. Substrate specificity is essential, given that the coordinated degradation of cellular proteins must be a highly regulated process for the cell to 3

survive. This pathway by which proteins are ubiquitinated and degraded by the proteasome is termed the ubiquitinproteasome pathway and is critical to not only the cell cycle but also the inflammatory response and antigen presentation.

CONTENT
2.1 Definition Of Huntingtons Disease HD is an autosomal dominant hereditary neurological disorder that was first described in 1872 by an American doctor, George Huntington. It happens because there is a mutation in huntingtin genes (HTT gene) which is located on the short arm of chromosome 4. In a person who doesn't have HD, the gene IT15 on chromosome 4p16.3 (identified in 1993), codes for a protein called huntingtin. Basically this means that the trouble begins at a gene on chromosome 4. In a normal person, the gene IT15 will contain between 11 and 34 repeats of the nitrogenous base triplet CAG. The CAG triplet encodes the amino acid glutamine. Therefore, the number of CAG triplets in gene IT15 equals the number of glutamine amino acids in the huntingtin protein. In people with HD, there are between 37 and 121 repeats of the CAG triplet. When this happens, it is called a stutter. This series of CAG repeats is called the polyglutamine region because it codes for several glutamine molecules. A person who has between 37 and 41 CAG triplet repeats may develop some of the symptoms of HD, but not necessarily the full-blown disease. The entire huntingtin protein is made up of over 3000 amino acids. This may be why just a few extra repeats causes only partial symptoms. People who have over 41 repeats almost always develop the disease; and the more repeats they have, the earlier the onset, and the worse the symptoms are.

Figure 3 Place of Huntingtin gene in chromosome

Figure 4 Repetation of CAG nitrogen base in HD patient The accumulation of mutant protein is a common feature of neurodegenerative disease. In Huntingtons disease, a polyglutamine expansion in the huntingtin protein triggers neuronal toxicity. Accompanying neuronal death, mutant huntingtin aggregates in large macromolecular structures called inclusion bodies. The function of the machinery for intracellular protein degradation is linked to huntingtin toxicity and components of this machinery colocalize with inclusion bodies. An increasing body of evidence implicates the ubiquitin-proteasome pathway in the failure of cells to degrade mutant huntingtin. The ubiquitin enzyme, cannot degrade all the mutant huntingtin protein properly because the amount of this protein is too much. And with an unknown system, somehow the ubiquitin-proteasome pathway degrades and fails to recognize the protein. So the E1 is unable to recognize the huntingtin protein causing the failure in its degradation. 2.2 Symptoms of Huntingtons Disease Huntington's Disease symptoms arise due to damage to the basal ganglia and the cortex of the brain. The basal ganglia is a small system in the middle of the brain that has a lot of control over movement. The basal ganglia consists of many parts, but the caudate, putamen, globus pallidus, substantia nigra, and the subthalamus are the major players in this system. The striatum is the name given to the caudate nucleus and the putamen together, and is the place where HD has its most severe. This slowly impairs a person's ability to walk, think, talk and reason.

Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an kinetic-rigid syndrome; they progress faster and vary slightly. The onset and rate of progression of the disease tends to follow a pattern within each family. The disease often progresses slowly, and the affected person may live for 15 to 20 years after the initial diagnosis. Symptoms: clumsiness or uncontrolled muscle movements (these movements are known as chorea) and rigidity which is usually a special characteristic of Huntingtons disease memory loss (especially of recent events) or confusion, changes in personality and mood that may include aggressive and antisocial behaviour, As the condition progresses, other symptoms of dementia appear. This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias

like Alzheimer's disease Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality difficulties with speaking and swallowing, weight loss, seizures, depression and anxiety may also occur Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy

2.3 Diagnosis of Huntingtons Disease 1. Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. 2. Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. 3. A physical examination, sometimes combined with a psychological

examination, can determine whether the onset of the disease has begun. 4. During pregnancy a woman can find out if her baby will have the disease with two tests: a. taking a sample of fluid from around the fetus (amniocentesis), b. by taking a sample of fetal cells from the placenta (chorionic villus sampling (CVS)). 5. How far the disease has progressed can be measured using the unified Huntington's disease rating scale which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments. 6. Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI), only shows visible cerebral atrophy in the advanced stages of the disease. 7. Functional neuro-imaging techniques such as fMRI and PET can show changes in brain activity before the onset of physical symptoms. 2.4 Epidimiology of Huntingtons Disease The worldwide prevalence of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, and is lower in the rest of the world, e.g. one per million people of Asian and African descent. 2.5 Management of Huntingtons Disease No cure or treatments that can modify the disease is currently available for HD. Therapy is focused on symptom management and supportive care in order to

optimize quality of life. Despite these difficult conditions, practitioners must be extremely aware on taking care of the patients with HD and their families.

If one of your parents has Huntington's disease, you have a 50-50 chance of getting the same disease during your life. A blood test can give appropriate result on detecting if you have the HD gene and whether you will develop the disease or not. Genetic counseling can help you weigh the risks and benefits of taking the test.

The best care is provided by an interdisciplinary team that addresses the broad physical and psychological needs of patients and families and manages to inform new issues as they arise through long-term follow-up.

There are some therapy that can be used to treat HD, those are: 1. Use of physiotherapy, occupational therapy, and home care may allow for prolongation of community living, although there is a dearth of supporting literature. 2. 3. Speech therapy for slurred speech and dietary services. A special diet such as high calorie diet is frequently needed because of the high metabolic requirements in patients with HD. 4. Gait and balance issues should be assessed by a physiotherapist, and a walker and/or wheelchair used as indicated to prevent falls. Hip protectors are recommended to decrease the risk of hip fractures, since falls are common in the late stages. 5. Dysphagia and aspiration pneumonia are common causes of death in patients with end-stage HD. The potential use of a gastric tube feeding and other end-of-life issues (e.g. home care, resuscitation, other aggressive medical interventions, guardianship, and advanced medical directives) should be discussed with the patient and family before motor symptoms and cognitive degeneration become severe, and before the patient loses the ability to communicate.

CONCLUSION
1. By catalysing limited or complete degradation of proteins, the UbiquitinProteasome System functions in many basic cellular processes. Thus, the UPS is essential for development and maintenance of all eukaryotic cells. This biological importance implies that the UPS is also inevitably involved in pathophysiological processes resulting in the development of many diseases. One of the diseases is Huntingtons Disease. 2. HD happens because there is a mutation in huntingtin genes (HTT gene) which is located on the short arm of chromosome 4. In people with HD, there are between 37 and 121 repeats of the CAG triplet that causing accumulation of mutant huntingtin protein that triggers neuronal toxicity. An increasing body of evidence implicates the ubiquitin-proteasome pathway in the failure of cells to degrade mutant huntingtin. The ubiquitin enzyme, cannot degrade all the mutant huntingtin protein properly. 3. Huntington's Disease symptoms arise due to damage to the basal ganglia and the cortex of the brain that has a lot of control over movement. This slowly impairs a person's ability to walk, think, talk and reason. The main symptom is chorea. 4. Diagnose of HD can be made through medical diagnosis, genetic testing, physical examination, psychological examination. In baby uses two tests: amniocentesis, CVS. How far the disease has progressed can be measured using the unified Huntington's disease rating scale. 5. The worldwide prevalence of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns, but has no corelation with sex. 6. The best care for HD patient is provided by an interdisciplinary team that addresses the broad physical and psychological needs of patients and families and manages to inform new issues as they arise through long-term follow-up.

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