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BIOCHEMISTRY OF PARKINSON'S DISEASE
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DOPAMINERGIC NEURONS Dopamine is produced in the dopaminergic neurons, one of dozens of cell types in the brain. Dopamine formation is this cell's unique function. Nearly all cell types reproduce. There are only a few cell types that don’t. One of these is the dopaminergic neurons - the cells involved in Parkinson’s Disease. So there is irreversible cell loss in Parkinson’s Disease. However, no study has ever demonstrated the widely held belief that there is considerable, and therefore overwhelming cell loss in Parkinson’s Disease. The studies previously claimed to show this have actually demonstrated greatly reduced cell activity rather than a loss of the cells themselves. They have used measures such as enzyme activity or the f-Dopa PET scan. Yet, neither of these actually measure cell loss. Despite this, claims of massive cell loss in Parkinson’s Disease widely persist.
DOPAMINERGIC NEURONAL GROUPS DOPAMINERGIC PATHWAYS Dopaminergic pathways, which are sometimes called dopaminergic projections, are neural pathways in the brain that transmit dopamine from one region of the brain to another. The neurons of the dopaminergic pathways have axons that run the entire length of the pathway. The major dopaminergic pathways in the brain are : the nigrostriatal pathway, the mesocortical pathway, the mesolimbic pathway, the tuberoinfundibular pathway, the diencephalospinal pathway, the incertohypothalamic pathway, neuroendocrine pathways, the olfactory pathway, and the visual pathway. DOPAMINE BIOSYNTHESIS The primary fault in Parkinson's disease is that, whatever the cause, there is insufficient dopamine. Dopamine is formed in the dopaminergic neurons by the following pathway:
The first step is biosynthesised by the enzyme tyrosine 3-monooxygenase [1.14.16.2] (which is more commonly called by its former name tyrosine hydroxylase). The following is the complete reaction:
So for L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and ferrous iron are essential. The activity of this enzyme is often as low as 25% in Parkinson's disease, and in severe cases can be as low as 10%. This indicates that one or more of the elements required for the formation of L-dopa are in insufficient quantities. The second step in the biosynthesis of dopamine is biosynthesized by the enzyme aromatic L-amino acid decarboxylase [4.1.1.28] (which is more commonly called by its former name dopa decarboxylase). The following is the complete reaction:
So for dopamine biosynthesis from L-dopa, pyridoxal phosphate is essential. The activity of the enzyme rises and falls according to how much pyridoxal phosphate there is. The level of this enzyme in Parkinson's disease can also be around 25% or even far less. COENZYMES INVOLVED IN DOPAMINE BIOSYNTHESIS Besides two enzymes being required for the formation of dopamine from L-tyrosine (L-tyrosine >>> L-dopa >>> dopamine), three coenzymes are also required. Enzymes are substances that will enable a specific chemical reaction to take place in the body. Coenzymes are substances that assist enzymes. Some enzymes (including those involved in dopamine biosynthesis) will not function without coenzymes. The three coenzymes involved in the formation of dopamine are : THFA (for L-tyrosine to L-dopa), pyridoxal phosphate (for L-dopa to dopamine), and NADH (for the formation of THFA and Pyridoxal phosphate). They are made from vitamins via the following means : Folic acid → dihydrofolic acid → tetrahydrofolic acid Pyridoxine → pyridoxal → pyridoxal 5-phosphate (this requires zinc as a cofactor) Nicotinamide NMN → NAD → NADH (or NADP) → NADPH G-PROTEINSIn order to relieve Parkinson's disease, dopamine (or dopamine agonists) must stimulate dopamine receptors, which must in turn stimulate the G proteins : L-tyrosine → L-dopa → dopamine → dopamine receptors (D2, D3, D4) > G proteins G proteins consist of three parts : alpha - beta - gamma, that are linked to each other. There are three types of beta unit (1, 2, 4), and seven types of gamma unit (2, 3, 4, 5, 7, 10, 11). However, they do not matter much to Parkinson's Disease. What matters to Parkinson's Disease are the alpha subunits, because it is actually these that ultimately relieve (or aggravate) Parkinson's disease. There are five types:
The sole purpose of dopamine (or dopamine agonists) stimulating dopamine receptors is to cause the alpha subunits (the active part of G proteins) to break away from the rest of the G protein. Once the alpha part of G proteins is released, via cyclic AMP, it takes the final action in the series of biochemical events. CYTOLOGICAL EFFECTS When L-dopa or dopamine is not biosynthesized properly in the dopaminergic neurons, as occurs in Parkinson's Disease, certain cytological effects can occur. This can result in the formation of Superoxide anion, Neuromelanin formation, Iron accumulation, the accumulation of Alpha-synuclein, and the formation of Lewy bodies. Superoxide anion The first step in the formation of dopamine is the biosynthesis of L-dopa from L-tyrosine. In Parkinson's Disease, largely due to inadequate cofactors, L-tyrosine and molecular oxygen do not completely form L-dopa. Consequently, the toxic partial reduction product of oxygen, the superoxide anion can be formed instead. Superoxide (O2-) is formed by the oxidation of ferrous ions (Fe2+) by dioxygen (O2). Neuromelanin When L-Dopa is unable to form dopamine it may instead lead to the formation and accumulation of neuromelanin, which is similar to the pigment melanin found in skin. It can do this via the enzyme peroxidase instead of the enzyme tyrosinase, which is usually responsible for melanin production, because tyrosinase does not occur in the dopaminergic neurons. Iron accumulation Iron is essential for the formation of L-dopa. So the deficiency of iron can cause insufficient L-dopa. Insufficient formation of L-dopa is the primary biochemical fault in Parkinson's Disease. It is a common compensatory mechanism in biochemistry for a cofactor such as ferrous iron to accumulate when the substance it facilitates the formation of is deficient. That is why instead of iron accumulation causing Parkinson's Disease, Parkinson's Disease can cause an accumulation of iron. Alpha-synuclein Iron accumulation also increases the aggregation of alpha-synuclein. Alpha-synuclein expression is regulated by iron mainly at the translational level. The superoxide anion can also be produced as a result of Parkinson's Disease when L-dopa is formed insufficiently. Superoxide is broken down to hydrogen peroxide (H2O2) by the enzyme Superoxide Dismutase. Hydrogen peroxide (H2O2) plays a dominant role in the aggregation of alpha-synuclein. So it is Parkinson's Disease, due to insufficient formation of L-dopa, that causes the aggregation of alpha-synuclein. Lewy bodies Lewy bodies are characterised by abnormal intraneuronal deposits (Lewy bodies) and intraneuritic deposits (Lewy neurites) of fibrillary aggregates and Lewy grains. Aggregated alpha-synuclein is the major component of Lewy bodies, Lewy neurites and Lewy grains and the primary cause of Lewy body formation. The deposits of alpha-synuclein in Lewy bodies colocalize with ubiquitin, which is the second major component of Lewy bodies.
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