Neurodegenerative Diseases: Huntington’s disease
Introduction
Neurodegenerative diseases are also referred to as Degenerative nerve diseases. In the life span of a neuron, there is progressive failure of structure or function which may also result to death of the neurons. The process is called neuron degeneration. Some of the diseases that result from neurodegeneration include Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. The main consequence of such diseases is that they worsen many of the human body activities like mobility, breathing, abstract thinking, emotional feelings, heart function, talking and balance. There has been ongoing research on the neurodegenerative diseases and recently, similarities have been found which are expected to increase the hope for common therapeutic advances that could prevent or intervene for most of these devastating diseases simultaneously. One of the major causes of neurodegenerative diseases is genetic mutations, especially in disparate genes. The purpose of this paper is to discuss Huntington’s disease but first an overview of the degenerative diseases.
Historical background of the Huntington disease
The earliest definition of the earlier Huntington’s chorea is dated in 1842 when Walters found it in a patient. The term Huntington’s chorea was by George Huntington who named the disease after himself in 1872. One of the characteristic of patients with Huntington’s chorea is the redundant choreatic movements, dementia and psychiatric disturbances mainly in middle aged adults from families passing the disorder from one generation to another (Roos 2010). The name just changed recently to Huntington disease (HD) as researchers gained more cognizant on the signs and far-reaching symptoms. The research on Huntington’s disease gained momentum in 1993 after the discovery of the Huntington disease’s gene, prior to which was the discovery of a linkage on chromosome 4 in 1983.
With these new discoveries, actual diagnosis for the disease was made possible, but since Huntington was one among many disease of polypeptide iterations of cytosine, Adenine, and guanine (CAG), this served as the basis for their study. CAG is the codon for the amino acid named glutamic and is the cornerstone for the DNA (Roos 2010). This development paved even further room for research on the treatment and currently, symptomatic treatments are accessible.
Process of protein folding
The most common forms of neurodegenerative diseases are the protein conformational disorders and some unusual forms of genetically hereditary disorders that entail deposition of protein aggregates in the brain (Nature reviews 2003). Proteins are very essential in the body and their proper functioning is dependent on their three dimensional structure determined by the sequence of the amino acid present. Protein folding, according to Fadiel et al (2007), is the process through which the polypeptides fold from original random nature to typical and functional three dimensional structures since each protein exist in a random coil or an unfolded polypeptide after the transformation to a linear amino acid from a sequential mRNA (Messenger Ribonucleic Acid).
In the conformational disorders, a given protein can fold into a stable substitute conformation, which more often than not results to aggregation and accumulation in tissues and fibrillar deposits which may differ in chemical and biological features depending on the whether the aggregation is intra-, or extra-cellular (Fadiel et al 2007). This is not always the case as there are instances of protein misfolding or incorrect protein folding which is associated with the multimerization of these proteins into unsolvable extracellular aggregates. The potential mechanism that involves misfolding and aggregation is the common cause of neurodegenerative diseases in the likes of Huntington’s disease among others.
Evidence for this cause was obtained from post-mortem neuropathological studies. According to Alois Alzheimer, neuritic amyloid plaques and neurofibrillary tangles are the characteristic causes where the amyloid plaques are extracullulary placed in the brain parenchyma and cerebral vessel walls with the main component being a 40- or 42- residue peptide while tangles are located in the cytoplasm of degenerating neurons and comprising aggregates. For patients with HD, the intranuclear deposits of a polyglutamine-rich version of Huntingtin protein are found in the brain (Nature science 2003).
An informal role of protein misfolding has also been identified in genetic studies (nature science 2003). The inherited forms of all the neurodegenerative disorders are associated with the transmutation of the protein mechanism of the fibrillar aggregates and such has been evident in Huntington Disease’s patients. Common evidence has been found in the generation of humans bearing mutant genes.
Protein misfolding
The determination of the structural necessities of conformational transforms leading to aggregation have been done using various protein chains and solution circumstances and the most common is the formation of amyloid by the Alzheimer’s Aβ protein (Hatters 2008). The earliest steps of misfolding and aggregation of Aβ is indicated by the interior region to hydrophobic amidst amino acid 17 and 21 where internal exchanges facilitate the hydrophobic exchanges in the assembly of Aβ and is common even for advanced aggregation of Aβ peptides with two or more amino acids hydrophobic in nature.
For Huntington diseases and other polyglutamine diseases, protein aggregation is not out of hydrophobic sequences but due to a hereditable expansion of codon for glutamine or CAG repeats. In vitro, Huntingtin aggregation is dependent on the length of the polyglutamine iteration (Nature reviews 2003). In Huntington disease, the polyglutamine has an amide group which gives the polar side chain and so has the potential to form a hydrogen bond with water. Alternatively, the polar zipper model explains interactions amidst proteins where β-sheets are formed and stabilized by collective strength of collaborative strength of corporative hydrogen connection of the amide of the glutamine residue. In summary, there are two main causes of fibrillar products: the polar hydrogen bonding involving the side-chain compilation and the hydrophobic exchanges.
Protein misfolding and aggregation has been associated with various environmental and genetic causes. One genetic factor is the mutation mechanism which results to conformational transformations and disease possibly subverting ordinary protein conformation, in support of misfolding and aggregation (Hatters 2008). Some ecological factors like the alterations of metal ions, oxidation stress or pH, pathological chaperone proteins, and macromolecular crowding alleviates chances of misfolding by acting as catalyst. In Huntington disease, aggregation process bears a resemblance to nucleation mechanism close to crystallization method (Nature reviews 2003). This process involves the formation of nucleus, protein oligomers, that facilitates increased aggregates growth which is characterized by slow lag phase that can be minimized by two alternatives namely: monomeric protein and fibrillar aggregates both of which occur concurrently and in dynamic equilibrium.
Mechanism for neuron death
The most typical aspect of the degenerative diseases is the discerning loss in neurons, alteration in the synapses and inflammation or irritation of the neurons. Nonetheless, the part of the brain affected differs from one neurodegenerative disease to the other (Nature reviews 2003). For instance, in Huntington disease, the loss of neurons is severe and in two stages. First it affects the neostriatum and later the cerebral cortex. For other diseases like the Parkinson’s disease, the neuronal loss occurs in the substancia nigra and also causes exhaustion of dopamine in striatum (Nature reviews 2003).
Causes of misfolding of Huntingtin’s gene
Huntington’s disease is and autosomal principally hereditary disease originating from a stretched out CAG replication on the small arm of chromosome 4p16.3 in the huntingtin gene. This gene is responsible for coding the huntingtin protein and on exon 1; the gene contains the CAG tract (quarrel 2008). The undomesticated-type of huntingtin gene contains a CAG repeat, coding for a polyglutanime stretch in the protein at that site in between 6 to 26 while Huntington’s disease is associated with at least 36 repeats and for more than 40, a clear clinical indication of the disease’s presence is felt. Within the range of 36 to 39 repeats results to an unfinished infiltration of Huntington’s disease or to what is called an onset.
In the range of 29 to 35, the transitional alleles are unstablized which means duplication of the gene may result to vulnerability to stretching out and on rare occasions they shorten. Such phenomenon is common especially in the male line of reproduction. First motor manifestations dictates the length of the CAG repeat and the onset age. The longer the repeat guarantees earlier stage of onset (quarrel 2008). In the case of Juvenile Huntington’s disease this repeat is more than 55. The CAG repeat duration provides no information about the cause, original symptoms or the length of the disease but a fast repeat normally results to with weight loss.
Effects of misfolding of Huntingtin gene
The major symptoms and signs of Huntington disease are motor, cognitive and psychiatric disturbances (quarrel 2008). Minor prevalent features include autonomic nervous system dysfunction, circadian- and sleep-disturbances, as well as unintended weight loss. Any person within the age of 30 to 50 year is liable for HD and the life span of the disease in a person can be 2 to 85 years although the mean duration for the disease is 17 to 20 years (quarrel 2008).. For most patients resulting to death, the main cause is the occurrence of pneumonia accompanied by suicide.
The effects of protein misfolding
Protein misfolding occurs as a result of the loss of three dimensional structure of the polypeptide protein chain leading to misfolded, partially folded or wrongly folded proteins states that are not in symmetrical to each other. Protein misfolding or peptides is as a result of genetic variants, transmutation and changes in intracellular surroundings for instance advanced aging. First, the misfolded protein or peptide is open to the elements of hydrophobic regions and interface with cell components.
This results to the failure of the intracellular mechanism to chaperone the misfolded proteins resulting to chaperon refolding or degradation of the enzyme, compartmentalization or formation of Russell bodies or aggressive, finally is the maturation of the fibrils or the out of order aggregations. When these three mechanisms fail, the chaperone is overloaded and results to the collection of misfolded proteins and the associated pre fabrilliar summative. This causes the cell membranes to waver the possibly due to the formation of non specific pores, hence the intracellular redox staus and ions spread is impaired. As a result, the patient suffers the loss of redox homeostasis resulting to the death of cells and the appearance of clinical indicators.
There are several conditions that favor protein aggregation some of which are the adjustment of equilibrium between rightly folded and partly folded molecules inclination towards the partly folded protein molecule or due to excessive spreading out of the misfolded protein as well as the entire surrounding partially folded molecules in the population. Such situations may result from changes in environmental factors or the alteration of chemicals ending up to the minimized conformational steadiness of the protein. On the other hand, some particular forms of mutations promote aggregation by encompassing the collection of the misfolded monomers kinetically, hence the formation of oligometric pre-fibrillar group.
Researches on treatment of misfolded proteins
Although the pathogenesis of Huntington disease is under investigation, several therapeutic methods are available for the treatment of the signs and symptoms with the purpose of improving life (Roos 2010). The main treatment involves the use of drugs prescribed as well as non medication advice. Motor signs are treated with the issue of dopamine blocking or Receptor agents for hyperkinesias or chorea. Other medications involve the management of violence and depression to contain these psychiatric signs. Psychiatric signs may also require on-medical interventions like occupational and physiotherapy, and speech therapy among others.
Motor
The transformations of motor are spontaneous and redundant and occur initially in distal margins like the fingers and the toes and in small muscles of the face which are most time and again invisible or seen as nervousness (Quarrell 2008). The common characteristic in everyday life is the staggering and unstable appearance of walking and with time the redundant movements are distribute to all other body muscles of proximal and axial locations (Roos 2010).
Choreatic movements become ever present and with no particular pattern of occurrence for the facial choreatic resulting to ongoing movements of the muscles of the faces like lifting of the eyebrow, or the head is bent when the one protrude their tongue with sulking lips (Roos 2010). As of the long back muscles, there is a caused extension in movement that results to problems of swallowing and talking which result to constant choking in some patients and later on the patient ceases to talk (Roos 2010). Dysarthria and dysphagia are also common occurrence and all patients develop hypokinesia, alkinesia and rigidity which result to slack in pace for all measures (Quarrell 2008).
In these states, the proteins lose pactness and their hydrophobic core is uncovered to the surrounding gel increasing the predisposition of the formation of ‘seeds’ or aggregation nuclei that provides a sort of template where other wrongly folded proteins are incorporated to the nuclei hence increasing its size and resulting to fabrillar aggregates Motor. The transformations of motor are spontaneous and redundant and occur initially in distal margins like the fingers and the toes and in small muscles of the face which are most time and again invisible or seen as nervousness (Quarrell 2008).
The common characteristic in everyday life is the staggering and unstable appearance of walking and with time the redundant movements are distribute to all other body muscles of proximal and axial locations (Roos 2010). Choreatic movements become ever present and with no particular pattern of occurrence for the facial choreatic resulting to ongoing movements of the muscles of the faces like lifting of the eyebrow, or the head is bent when the one protrude their tongue with sulking lips (Roos 2010). As of the long back muscles, there is a caused extension in movement that results to problems of swallowing and talking which result to constant choking in some patients and later on the patient ceases to talk (Roos 2010). Dysarthria and dysphagia are also common occurrence and all patients develop hypokinesia, alkinesia and rigidity which result to slack in pace for all measures (Quarrell 2008).
Reference
Fadiel et al (2007). Modern Pathology. Bentham Science Publishers Ltd. Current protein and Peptide Science. Vol 8 (1).
Hatters D (2008). Protein misfoldings inside cells.University of Melbourne. Melbourne: Australia.
Nature reviews (2003). Neuroscience. Vol. 4.
Quarrel O (2008). Huntington’s Disease. Oxford University Press. Oxford: UK. From http://books.google.co.ke/books?id=2hWGB0zimogC&printsec=frontcover&dq=huntington+disease&hl=en&ei=vzPDTbLQFIKdOtmizZ0I&sa=X&oi=book_result&ct=book-preview-link&resnum=2&ved=0CEkQuwUwAQ#v=onepage&q&f=false.
Roos R (2010). Huntington’s disease: A Clinical Review. Orphanet Journal of Rare Diseases.
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