The Biochemistry Mechanism!

As it’s been mentioned many times that the Parkinson’s disease is the result of dopamine deficiency due loss of dopamine producing neurons in the Substantia Nigra of the brain, so for starters, let’s take a look at the biochemical mechanism of dopamine degradation.

Dopamine is degraded by 2 enzymes:

1)      MAO-A, Monoamine oxidase A

2)      COMT, Catechol-O-methyl-transferase

MAO-A, is located on the outer membranes of mitochondria within neurons and is present primarily in nerve terminals and glia in the brain. COMT on the other hand, is produced by neurons in the brain.
Ultimately, degradation of dopamine forms Homovanillic acid as the final product.

An increased amount Homovanillic acid has been found in Parkinson affect individuals and identified as a biomarker in Parkinson’s disease.

Vanillylmandelate, also identified as a biomarker, is the final product of Norepinephrine degradation. This acid was found in increased amounts in affected individuals with the disease.

Both dopamine and norepinephrine are catecholamines, thus the pathway for both are analogous.

Do note that Monoamine oxidase and catechol-O-methyltransferase can act in either order. First, Norepinephrine is metabolized by MAO to form an aldehyde group. The aldehyde group formed by monoamine oxidase is then oxidized to Vanillylmandelate, an acid, by aldehyde dehydrogenase.

Free radicals

Free radicals are very reactive and contribute to oxidative stress. It also damages neurons when present in high concentrations by targeting parts of the cell such as proteins, DNA, as well as the cell membrane by stealing electrons through oxidation. 

The diagram below show how free radicals are formed from MAO and COMT metabolism but, specifically from MAO metabolism.

 

 

 

Monoamine oxidase contains a flavin coenzyme. The enzyme first abstracts two electrons from the substrate dopamine. The first electron abstraction converts both dopamine and the enzyme to free radicals. On the enzyme, the unpaired electron remains with the Flavin.

The second electron abstraction then converts dopamine to a Schiff base, which is then hydrolyzed to an aldehyde and free ammonia. Schiff base is another name for an imine functional group. Schiff base is formed from the condensation of an amine group with the carbonyl group of an aldehyde or ketone, as shown in the figure below. 

Finally, MAO itself is re-oxidized by oxygen, forming H₂O₂ free radical in the process. Free radicals progressively damage cells, resulting in a loss of dopamine producing cells, the primary cause of Parkinson's disease.

Also, Dopamine acts as a neurotransmitter but at the same time it is very good metal chelator and electron donor to generate toxic free radicals. It has a high tendency to coordinate with Cu²⁺ and Fe³⁺ reducing metals to initiate Fenton’s chemistry and as a result, generating H₂O_2.

_{Fenton’s chemistry}

 

Fe³⁺ + •O₂⁻ → Fe²⁺ + O₂ (Step I)

Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + •OH (Step II)

Combining step I&II

•O₂^- + H₂O₂ → •OH + HO^- + O₂



 

_{Alpha-synuclein mutation in Lewy bodies} 

Alpha-Synuclein, a protein, was found in the Lewy bodies. Mutations in this protein plays a part in negatively modulating dopamine activity, initiating the interaction of dopamine with iron, giving rise to ROS production.

Apha-Synuclein protein

As you can see from the diagram below, besides the production of ROS, alpha-synuclein, oxidized and aggregated results in either Lewy bodies or apoptosis of cells in the brain.

  

Misfolded alpha-synuclein proteins converted into pathological oligomers and higher order aggregates that eventually form fibrils and the Lewy body itself. 

As seen from the last diagram, mutation in gene Park7 may also result in disrupted chaperones function, therefore unable to modulate the structure of alpha-synuclein, activating cell death pathways (2). Apart from that mutations may too result in chaperone molecules become sequestered in Lewy bodies resulting in leading to chaperone depletion. This might also be directly responsible for cell death (3)

 

 

 

That’s all for today! Hope that you’ve learnt something more and stay tuned to this space for frequent updates on the disease! J