The biochemistry of Parkinson's Disease

THE BIOCHEMISTRY OF PARKINSON'S DISEASE

The following is taken from a complete biochemistry of Parkinson's Disease. Summaries on each aspect of the biochemistry of Parkinson's Disease will be added to the Forum over time part by part.

PART 1 : DOPAMINE SECRETION

The primary fault in Parkinson's Disease is that, whatever the cause, there is insufficient dopamine. Dopamine is produced in the dopaminergic neurons in the brain. It is widely claimed that there is massive loss of dopaminergic neurons in Parkinson's Disease. However, although that is true in some exceptional conditions, those studies claimed to prove this actually demonstrate that there is a massive loss of cell activity rather than a massive loss of cells. So in idiopathic Parkinson's Disease, the cells remain but they are greatly reduced in their activity.

The dopaminergic neurons have many functions. However, they have only one unique function, and that is the secretion of dopamine.

Dopamine is formed in the dopaminergic neurons by the following pathway :

L-tyrosine >>> L-dopa >>> Dopamine

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 :

L-tyrosine + THFA + O2 + Fe2+ >>> L-dopa + DHFA + H2O + Fe2+

So for L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and ferrous iron are essential.

Studies on this enzyme, particularly the Nobel prize winner Udenfriend's study (Journal of biological chemistry [1964] 239 : 2910), showed that when some of the required elements for the formation of dopamine were eliminated, there was a massive reduction in the amount of dopamine formed. The relative amounts of dopamine produced were :

13.0 (with everything)
2.8 (without Fe2+)
0.3 (without THFA)
0.0 (without L-tyrosine)

The amounts of L-dopa formed were also in proportion to the amount of either L-tyrosine, THFA (tetrahydrofolic acid), or ferrous iron. As either of these substances increased or declined in quantity, so did the amount of L-dopa produced.

The level of activity of this enzyme has been found to be as low as 10% in people with Parkinson's Disease, which indicates that one or more of the elements required for the formation of L-dopa are in insufficient quantities.

Clinical studies carried out in order to correct a potential deficiency of tyrosine hydroxylase have used substances known to stimulate it : L-tyrosine, ferrous iron, THFA. All were shown to be beneficial to Parkinson's Disease. L-tyrosine in sufficient quantities was shown to rid 70% of symptoms. Ferrous iron was shown to rid 10% to 60% of symptoms.

The second step in the biosynthesis of dopamine is biosynthesised 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 :

L-dopa + pyridoxal phosphate >>> dopamine + pyridoxal phosphate + CO2

So for dopamine biosynthesis from L-dopa, pyridoxal phosphate (which is made from pyridoxine) 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 be around 25%. So it is less of a problem in Parkinson's Disease, but is still in quantities insufficient enough to cause Parkinson's Disease symptoms.

REFERENCES :

Tyrosine hydroxylase : Journal of biological chemistry [1964] 239 : 2910, Archives of biochemistry and biophysics [1967] 120 : 420, Nature [1983] 302 : 830, Comptes rendus academie des sciences [1986] 302 : 435.

Dopa decarboxylase : Journal of biological chemistry [1948] 174 : 813, Journal of biological chemistry [1957] 227 : 617, Journal of biological chemistry [1962] 237 : 89, Hoppe-Seyler's zeitschrift fuer physiologische chemie [1963] 332 : 70, Proceedings, national academy of sciences USA [1972] 69 : 343.

Clinical studies : Comptes rendues academie des sciences (III) [1989] 309 (2) : 43, Journal of neural transmission [1986] 67 : 287, Early diagnosis and preventive therapy in Parkinson's Disease [1989] : 323. Advances in neurology 40 : 463, Proceedings, Japan academy series B [1982] 58 : 283.