shutterstock_685870705.jpg

THE BRAIN PLAGUE

Victoria Stanisławska

Parkinson’s disease is the second most common neurodegenerative disease right after Alzheimer’s. Symptoms can be motor, for example, tremors and muscle rigidity, or non-motor, such as loss of smell or issues of the digestive tract. In most cases, non-motor symptoms are present even decades before onset motor symptoms.

Where does it all originate?

The pathological proof of the development of the disease is visible degeneration of substantia nigra pars compacta. Substantia nigra is Latin for “black substance,” this name is given, due to its pigmentation. Substantia nigra is present bilaterally on both sides of the brain. Its main role is regulating motor movements. The substantia nigra is made up of substantia nigra pars compacta and substantia nigra pars reticulata. The substantia nigra pars compacta has a dark colour in a healthy patient due to a large number of dopaminergic neurons that have high levels of neuromelanin (a dark pigment). Dopamine neurons are mostly found in the substantia nigra pars compacta, whilst substantia nigra pars reticulata has more GABA neurons. GABA (gamma-Aminobutyric acid) is the most common inhibitory neurotransmitter in the mammalian brain, it is present at 30 - 40% of synapses.

Unknown-5.tiff

The image above represents the “human postmortem bilateral midbrain” of a normal individual (A) and one suffering from Parkinson’s disease (B). As you can see, the SNpc is darker in the unaffected individual. The number of dopaminergic neurons in picture B present at the SNpc is significantly reduced, which leads to motor dysfunction and associated issues.
As there is a lack of dopamine in the brain, drugs are often administered. These drugs mimic the neurotransmitter as they have a very similar structure to dopamine and can be used to treat symptoms; an example is L-dopa (levodopa) which even in some cases led to the development of pathological gambling. Levodopa is a precursor of dopamine; it is able to cross the blood-brain barrier. Dopamine is linked to addiction and impulsivity as its release is associated with activities in which there is an uncertain reward and during pleasant activities such as gambling, listening to music or perhaps exercising. This promotes risk-taking behaviour and upping up the stakes to maximize the potential satisfaction of reward.

Unknown-6.tiff

What happens in the rest of the brain?

In most Parkinson's disease patients, inside neurons, there are clumps of misfolded proteins that are most commonly Lewy bodies which in the core consist of specific proteins that are surrounded by misfolded alpha-synuclein. Alpha-synuclein is most commonly present in the presynaptic neuron axonal terminals but is also present in the heart and other types of tissues. The misfolded alpha-synuclein joins together with others to create longer fibrils or oligomers. Research completed by Professor David Dexeter at Imperial College London proved that this misfolded alpha-synuclein is neurotoxic and hence leads to neurodegeneration. Usually, the excess of the undesired type of protein would be cleared away through cell homeostatic mechanisms however, these mechanisms become negatively influenced by the presence of the misfolded alpha-synuclein and lead to its accumulation.

Additionally, mitochondria which generate most of the organism’s short term chemical energy storage in the form of ATP (adenosine triphosphate), are usually cleared away once they become old or damaged and then become replaced so that biochemical reactions can still be carried out. In Parkinson’s patients, this system does not function properly, and the old and damaged mitochondria accumulate at the synapse and electrical impulses can no longer be transferred as efficiently, which leads to the development of symptoms.

Microglia absorb the resulting cellular debris of the dead neurons; this triggers an immune response that causes a release of inflammatory cytokines which are small proteins that then activate both astrocytes (glial cells that assist the blood-brain barrier) and surrounding microglial cells. These then release more chemicals that negatively impact neurons and lead to their death.

Treatment and cure

No cure for Parkinson’s disease had been yet developed, although there are treatment plans that can help diminish symptoms. Such can include deep brain stimulation or medication such as Levodopa. Scientists believe that there are several factors that must compound together to lead to Parkinson’s disease, this can be interpreted as an advantage since it gives many potential targets for prospective drugs.

Bibliography:

  1. Nature. (2019, December 16). Understanding Parkinson’s disease [Video]. YouTube. https://www.youtube.com/watch?v=ckn9zybpYZ8

  2. Michael- Titus, A. M. T., Revest, P. R., & Shortland, P. S. (2010, January 1). DEMENTIA. ScienceDirect. https://www.sciencedirect.com/science/article/pii/B9780702033735000149

  3. GABAergic neuron markers | Abcam. (2022, January 20). Abcam. https://www.abcam.com/neuroscience/gabaergic-neuron-markers-and-their-functions

  4. Wong, Y., Krainc, D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23, 1–13 (2017). https://doi.org/10.1038/nm.4269

  5. GABAergic neuron markers | Abcam. (2022, January 20). Abcam. https://www.abcam.com/neuroscience/gabaergic-neuron-markers-and-their-functions

  6. Wc, K. (1992, April 1). When does Parkinson’s disease begin? Abstract - Europe PMC. https://europepmc.org/article/med/1350072

  7. 2-Minute Neuroscience: Substantia Nigra. (2015, December 24). [Video]. YouTube. https://www.youtube.com/watch?v=JJ6YB4674GQ

  8. Celada, P., Paladini, C., & Tepper, J. (1999). Gabaergic control of rat substantia nigra dopaminergic neurons: role of globus pallidus and substantia nigra pars reticulata. Neuroscience, 89(3), 813–825. https://doi.org/10.1016/s0306-4522(98)00356-x

  9. Parkinson’s UK. (2022, January 5). Parkinson’s UK –. Medium. https://medium.com/parkinsons-uk

  10. Stefanis, L. (2019, September 1). How is alpha‐synuclein cleared from the cell? Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.14704

  11. Zaliteri, M. Z., Longhena, F. L., Pizzi, M. P., Missale, C. M., Spano, P. S., & Bellucci, A. B. (2015, March 31). Mitochondrial Dysfunction and α-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First? NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396726/

  1. Figure 1:  Motor and Non-Motor Features of Parkinson’s Disease – A Review of Clinical and Experimental Studies - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Fig-1-Massive-loss-of-midbrain-dopaminergic-neurons-in-the-substantia-nigra-pars_fig1_223964711 [accessed 21 Jan, 2022]​

  2. Figure 2: Moore, S. (2020, February 3). Role of Alpha-Synuclein Proteins in Disease. News-Medical.Net. https://www.news-medical.net/life-sciences/Role-of-Alpha-Synuclein-Proteins-in-Disease.aspx

  3. Front picture: https://theconversation.com/parkinsons-disease-scientists-find-the-earliest-roots-in-the-brain-119030