Talk:Introduction to Parkinson's Science/Draft design of Section 2

An introduction to the science behind Parkinson’s for those new to it – and maybe also relatively new to biological concepts
Start from where they are.

At diagnosis Parkinson’s patients present with primary symptoms – movement difficulties – tremor, stiffness, bradykinesia.

First question: Why? Simplistic answer: Basically too little dopamine in a certain part of the brain.

Supplementary questions arise from here and more questions keep on arising. Here is a possible sequence of early questions and how they may be addressed: What is dopamine? A neurotransmitter. Explain neurotransmitters. Explain that dopamine is one of many neurotransmitters. It is used in several parts of the brain. In some parts it is associated with pleasure/feelgood. In Parkinson’s it transmits messages related to control of movements. Explain that most movements are complex, involving many muscles. These movements have to be coordinated so that muscles contract or relax at the right time and others don’t. All controlled by bundles of cells at the base of the brain called the basal ganglia. It is important that dopamine is produced to convey messages from nerve cell to nerve cell and Parkinsonian symptoms arise if it is not.

Deeper level explanation: The other neurotransmitters especially glutamate and Gaba. The main basal ganglia and the main connections between them and how they connect to the motor cortex. More advanced: Peter Magill’s work (Oxford) on oscillations.

Why is there insufficient dopamine? Death of cells in the substantia nigra. About 80% have to die before symptoms appear.

Why do neurons die? This opens up a major section on causes of dopamine cell death and would go on to deal with strategies to prevent it. It would also lead to a discussion of cell-replacement strategies.

What about other symptoms of Parkinson's? Describe other symptoms of Parkinson’s especially non-motor: bladder and bowel, olfaction, speech and swallowing, depression, dementia. From considering the life cycle of Parkinson’s to the Braak staging hypothesis and the evidence for it beginning in the Enteric Nervous System and in the myocardial nerves.

What's really going on underneath? This leads to a discourse on the pathological signs – alpha-synuclein deposition. This will require an explanation of basic biochemistry. A discussion of proteins – that there are so many different ones which do all the essential things in the body. That they are expressed by the genes. That differences in their chemical composition lead them to having different shapes and that a combination of their chemical composition (functional groups) and their shapes determine how they will interact with other proteins and therefore how they will function.

Why is alpha-synuclein important? Alpha-synuclein is present in many cells and its function is not fully known but it appears to be involved in certain specified ways. The problem arises when molecules start to join together firstly as small oligomers and then as as higher order aggregates. It appears that some of the small oligomers are toxic rather than the aggregates. The aggregated forms could be an attempt by the body to remove the toxic forms. The question is why the normal garbage collection systems are not able to remove the toxic forms. An explanation of autophagy, the UPS and the innate and adaptive immune systems could be linked here..In some cases it might be a fault in one of these systems that allows Parkinson’s to develop.

There is also a link here to inflammation and to mitochondrial dysfunction.

Why am I given certain drugs and what do they do? People want to know about the drugs they have to use and what they are meant to do. They are almost entirely for dopamine replacement/conservation.

Levodopa. Works by being converted to dopamine. Link to description and chemical formulae for tyrosine, levodopa, dopamine, adrenaline, noradrenaline. Discussion of decarboxylase action. Also carbidopa and COMT and MAOB inhibitors to prolong lifetime of dopamine. Duodopa.

Dyskinesia as side effect.

Dopamine agonists. Activate dopamine receptors. Deep Brain Stimulation. Explanation about how it works. (Also link to Peter Magill's work above)

What other treatments are being researched? Other potential treatments:

Neuroprotective strategies and why.

Inflammation, anti-inflammatories and immunology

Antioxidants and why. Discussion of oxidative stress.

Vaccination against and disaggregation of alpha-synuclein

Growth factors. GDNF etc.

Transplantation.

Exercise – symptomatic treatment or disease modification?

Other causes that may suggest other effective therapies:

Genetics

Mitochondrial dysfunction.

What are the current hypotheses about the causes and mechanisms of Parkinson's? Overview of aetiology and pathogenesis – towards a unified theory.

Include hypotheses for the way it spreads (incl prion-like process)

What are the main areas of Parkinson's Research and how do they fit together?

Understanding the disease.

Model systems – in vitro, in vivo, animal models, use of iPSCs.

Genetic modification

Toxicology, pharmacology, biochemistry, proteomics, metabolomics

Drug screening

Epidemiology

Basic, lab-based research vs clinical trials and large scale surveys

Search for biomarkers for early diagnosis and biomeasures for rate and stage of disease progression.

Biosamples, scanning, rating scales, etc

Etc, etc

Sub structure of topics

Link this above narrative flow to the following substructure of topics from appropriate points in the above

Cells and Cytology

DNA and Genetics The CNS
 * Back ground (Discovery, Definition, Cell Theory)
 * Cell Properties (Cell Types, broad classification)
 * Types of Organism (Archea, Bacteria, Complex cells)
 * Features of Prokaryotic Cells (Table with added Notes)
 * Features of Eukaryotic Cells (Table with added Notes)
 * Protein Formation
 * Cell Division
 * Mitosis
 * Viruses (esp re genetic engineering)
 * Prions (only relating to possible prion-like spread in PD)
 * Nucleotides
 * Amino Acids
 * Polypeptides
 * Proteins
 * Gene
 * Chromosomes
 * Meiosis
 * Mutations
 * Nerves and Neurology
 * Neurons (components)
 * Signal transfer
 * Microtubules
 * Neurotransmitters

Basal Ganglia

Parkinson’s Disease (Mainly covered in main section)
 * Description
 * Symptoms
 * Lewy Bodies
 * Pathology
 * Levodopa
 * Treatment

Etc, etc

Further Reading

References