Parkinsons disease is a very common disease normally found in the individuals above the age of 70 years. Basically, it is an neurodegerative disease in which there is loss of nerve cells present in the substantia nigra in the mid brain. studies showed that a very low percentage of Parkinson`s disease patients were found below the age of 50 but on other hand percentage of patients having Parkinson`s disease increase gradually above the age of 75 to 80,, which gives an very clear indication that Parkinson`s disease is an age related disease. Parkinson`s disease is very slow progressive disease in which there is an gradual degeneration of neurons present in substantia nigra as long as the degradation of these neurons progresses it causes a reduction in the level of dopamine neurotransmitter, basically dopamine in our brain is produced to counter balance the excitatory effect of acetylcholine in the brain but in case of Parkinson`s disease there is an decreased level of dopamine due to which the excitatory neurotransmitter acetylcholine dominates and causes certain problems like ; tremors, slowness of movements, stiffness of joints, bodies balance problems, postural deformities etc, for basic treatment of parkinsons disease a precursor of dopamine known as levodopa is used in the treatment of Parkinson disease which has given an promising improvement in the symptoms of Parkinson`s disease patients. Critical conditions of Parkinson`s diseases are treated with the help of planting certain electrods to fullfill the damage neuronal circuits which stimulates the electrical flow with in the neurones -(2). Studies has also revealed that approximately there are 400,000 nerve cells present in our brain and these nerve cells start pigmentation after birth and a 100% pigmentation starts in the age of 18, but the symptoms of Parkinson`s disease can be analysed when approximately more than 70% of nerve cells die, but a normal rate of nigral cell death is approx 2,400 per year, so according to calculation an individual can live unaffected by Parkinson`s disease up to the age of 120 years but in clinical conditions its not like that, the death of nigral cells get acclerated, and still the proper mechanism of cell death is still not known and the concept behind the accelerated death of nerve cells is also not clear, but this accelerated death seems to be an result of combination of genetic susceptibility and enviourmental factors. According to analysed data these hereditary forms of disease has its impact over 4% of Parkinson`s disease patients who acquire this disease below the age of 50 years.
Alpha synuclein :-it is a very small (14 KDa) protein, which consist of 140 amino acids-(4) both cystine and trypotophan are not present-(5) and highly conserved in nature, found normally in different regions of brain. During the postnatal murine development of brain the production of alpha synuclein in our brain gradually increases, it also increases during the period of song learning in zebra finch, both these evidences showed that their is role of protein in
There are three regions according to which alpha- synuclein can be divided, First region consists of residue 1 â€" 60 having four disordered 11 amino acids repetitions with motif (KTKEGV). Second region consist of 61 â€" 95 residues, which consist of two added repeats along with a highly amyloidogenic region. And third region consist of 96 â€" 140 residues having highly charged C- terminals.(5)
Characterization of amino acid sequences of alpha synuclein is done by its six repeats in polypeptide, constituted by N-terminal, having residue 1 to 95, it also consist of an acidic carboxyl- terminal region having residue 96 to 140.
A purified alpha synuclein, structurally belongs to a category of unfolded proteins, which consist of very less or completely absent structural configuration in physiological conditions. The absence of any folded structure was correlated to low hypophobicity and presence of high net charge.---(3)
1.2) Lewy bodies pathological hallmark of Parkinson`s disease:-
A basic concept behind the neuronal damage in Parkinson`s disease is the formation of lewy bodies ,which are dense protein plagues / inclusions(2) spherical in shape, basically found in the surviving cytoplasm of nigral cells(5) ,which affects the nerve cells in the subtantia negra and interferes with release of proper quantity of dopamine into the brain . alpha synuclein are the primary building blocks of lewy bodies, although the proper exect mechanisum or function of these inclusions bodies formed in our brain is not known clearly from past many years.
The importance of the alpha synuclein as a major component of lewy bodies was first explained in certain genetic studies. In the category of familial Parkinson`s disease mutation of alpha synuclein gene product was found to be the major causative agent . it is also proven that mutant alpha synuclein protein acts like a very selective cytotoxic agent over dopaminergic neurons by using a rat model in which an engineered virus was injected in a rat brain. (2)
1.3)Oligomers:-
Currently the theory behind the origin of Parkinson`s disease placed this disease between a large category of neurodegenerative disease occurred due to the misfolding of proteins. And the protein by the misfolding of which Parkinson`s disease occurs is the slpha synuclein, in the Parkinson`s disease their is higher level of misfolded alpha synuclein is reported, which further leads to a formation of neurotoxic aggregates called Oligomers .
It is also noticed that any type of mutation in alpha synuclein make it more susceptible to acquire any abnormal configuration as compare to its wild type. A slow but continous accumulation of misfolded alpha synuclein molecule readly supports the process of olgomeization which further acts as a toxic species for neuronal cells.(2)
1.4) Fibrills :-
Some important previous studies already performed in this field of neurodegenerative diseases :-
Understanding of molecular events , which basically takes place into the protein aggregation and how aggregation effects our body mechanism by taking place into the substantia nigra and study of conformational changes which takes place along with beta-strands formation. These all studies are performed by( G Brent Irvine and Omar MEI- Agnaf, et. al. In 2008.)---(6).
Analysis of central role of alpha synuclein fibrillization in Parkinson`s disease pathogenesis by using mouse and drosophila models , to develop more advance and exact knowledge for the process of fibrillization which takes in various neurodegenerative diseases and using this knowledge in developing more effective and safer therapeutic techniques for the treatment of neurodegenerative. This study was carried out by ( Matthew S. Golberg and Peter T. Lansbury Jr ).â€"(7).
Characterization of amylodogenic protein states using spectroscope, in this article several studies are analysed in contrast of misfolding of amyloid proteins , oligomerization and growth of amyloid fibrils , in the amyloid fibrils studies protein characterization techniquies were used and by the use of real time detection techniques oligomeric precursor states were analysed , with the help of thioflavin- T for fluorescent staining.above studies were carried out by (Mikael Lindgren and Per Hammarstrom)----(8).
Study of defective aggregation in alpha synuclein mutant gene , which inhibits the fibrillation in the Parkinson`s disease. Basically three genes were detected ( A30P , a53T & E46 K) having missence mutation which can cause the accelerated fibrillation and oligomerization of alpha synuclein protein. It is also detected that intracellularly higher concentrations of wild type alpha synuclein due to duplication and triplication also plays very important role in inherited Parkinson`s disease.Many evidences were also found which indicates a
