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

Cause of Parkinson’s disease

Research team uncovered the causes of Parkinson's disease 

Good morning, Martians folks! There's good news to start the day off! The weather forecast predicts that the Milky Way can be clearly viewed tonight without the use of a telescope :)

Here’s a quick update about Parkinson’s disease. After 2 weeks of collaboration and intensive research, the causes of this disease has been uncovered!

Parkinson’s disease, is a disease resulting from the continuous degradation of neurons in the Substantia Nigra of the brain. A vital brain chemical messenger dopamine, produced by neurons in the Substantia Nigra, allows communication between the Substantia Nigra and the Corpus Striatum. This communication aids in movement of smooth, as well as balanced muscle. Absence of dopamine leads to the unusual nerve functioning and inability to control body movements as seen in Parkinson's disease.

Based on research results produced by the Martian research team, the occurrence of Parkinson’s disease may be due to the several factors which include genetic and environmental factors.

Particular genetic mutations have been identified by our researchers to be the cause of Parkinson's disease. In most cases, it is not inherited directly. However, the research team has discovered that people with an affected first-degree relative, such as parent or sibling, have an increased chance of four to nine percent of developing the disease. Some genes which play a role in dopamine cell function are mutated. Mutations in genes for LRRK2, PARK7 (DJ-1) and PINK1 had lead to the development of Parkinson’s, even at an early age. 
There are 4 MAIN CAUSES of Parkinson's disease but first...



Let's introduce the few genetic mutations

Gene 1 : LRRK2, Leucine-rich repeat kinase 2

This gene is active in the brain and provides instructions for making protein dardarin. Dardarin comes from the basque word " dardara " which means tremor, as seen as a characteristic of the disease.

The LRRK2 gene is located at 12q12 (chromosome 12 position 12) as shown in the diagram below.
More specifically it is located from base pairs 40,225,010 to 40,369,284

Mutations in the LRRK2 gene results in Parkinson’s disease. The mutation changes the shape and structure of the protein, resulting in the disease. For this specific gene mutation, single amino acids in the protein are replaced.  There are a 3 common areas of mutation for the LKRR2 gene:

1) Mutation Arg1441Gly :
Amino acid arginine is replaced with amino acid glycine at protein position 1441.

2) Mutation Gly2019Ser :

Amino acid glycine is replaced with amino acid serine at protein position 2019.

3) Mutation Gly2385Arg :

 Amino acid glycine is replaced with amino acid arginine at protein position 2385.

Gene 2 : PARK7, Parkinson Protein 7

The PARK7 gene is located at 1p36.23 (Chromosome 1, position 36.23) as shown in the diagram below.

More specifically, it is located from base pairs 7,961,653 to 7,985,282

Like all genes, this gene codes for a protein, Protein deglycase DJ-1.

The gene plays a crucial role in mitochondrial cell protection and reduces the effect of oxidative stress induced by calcium entry into the dopaminergic neurons of the Substantia Nigra Pars Compacta. In simpler terms, it acts as an oxidative stress sensor, redox-sensitive chaperone and protease.

There are 2 possibilities as to how the mutation might have caused the disease :

1) Mutation disrupts the chaperone function, leading to a toxic buildup of misfolded or damaged proteins, eventually resulting in cell death.
 

2) Since Nerve cells that produce dopamine are very affected by oxidative stress, the mutation might have inhibited the ability of the protein's protection mechanism against oxidative stress, resulting in free radicals damaging the neurons. Since progressive loss of dopamine producing neuron is the main cause of the disease, communication between brain and muscles weakens and eventually the brain is unable control muscle movement.

EARLY ONSETS OF PARKINSONS DISEASE : 

Gene 3 : PINK1, PTEN induced putative kinase 1
 

The PINK1 gene is located at 1p36 (chromosome 1, position 36), as shown in the diagram below.

More specifically, it is located from base pairs 20,633,454 to 
20,651,510

This gene also protect cells from stress-induced mitochondrial dysfunction.

Early-onset Parkinson diseas generally begins before the age of 50. With the mutation, it will result in reduced PINK1, leading to mitochondrial malfunction. Therefore, the loss of these cells too, result in weak communication between the brain and muscles. Eventually, the brain becomes unable to control muscle movements.

 

2) Environmental factors may also be the cause of Parkinson’s disease. The research team has suggested that either internal or external toxins may have selectively wiped out dopaminergic neurons, leading to the disease. Exposure to toxins such as manganese, carbon monoxide, carbon disulphide and some other pesticides may increase risk of getting Parkinson’s disease.

3) Like the mutation of PINK1 mentioned above, oxidative stress is also believed to cause Parkinson’s disease. The formation of free radicals can be found normally in the brain and body but typically, both have mechanisms to remove them. In people suffering from Parkinson’s disease, the mechanisms maybe not be effective or there may be high production of free radicals. These free radicals contribute to oxidative stress. Environmental toxins may have also possibly contributed to the abnormal production of free radicals hence, leading to Parkinson’s disease. 

4) As mentioned previously, Lewy bodies, which are unusual clumps of brain protein, holds an important clue to the cause of Parkinson’s disease. Alpha-Synuclein, a protein, was found in the Lewy bodies where researchers believe to be of most importance. However, not much information on the protein has been gathered and researchers are still in the midst of investigating.

That is all for today's post folks!

A gentle reminder to catch the stunning view of the Milky Way tonight. Have a great day ahead and stay tuned for more interesting updates on Parkinson’s! :)