Gretchen Amphlet Parkinson's UK lecture 2013 - Part 4

For Part 1: http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture.html

For Part 2: http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture_24.html

For Part 3 - http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture_25.html


Conclusion – prospects for treatment

Identifying mutations is a crucial first step toward new treatments for Parkinson’s. Understanding which genes are mutated in sufferers and how the protein is affected leads to understanding how the function of the cell is disrupted. Once this is known, drugs can be potentially designed to counteract the affect of the mutant protein and prevent nerve cells dieing. This could introduce the idea of “personalized medicine”; a specific mutation is treated with a specific drug. Another possibility is that a group of related diseases (e.g. neurodegenerative), although caused by mutations in different genes, affect the same function of nerve cells. Therefore, drugs can be designed to affect the specific cellular process more generally and not the mutated protein itself.

These approaches are dependent on understanding the genetics of Parkinson’s; it is crucial that such research is supported.

Gretchen Amphlet Parkinson's UK lecture 2013 - Part 3

For Part 1: http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture.html

For Part 2: http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture_24.html

Understanding why nerve cells die in Parkinson’s - Case Studies

What are the faulty proteins doing to cause nerve cells to die? Two studies were presented that examined the role of two genes.

1. a-synuclein

When proteins are made the string of amino acids fold around each other to form a 3D shape: the shape determines a protein's function. Mutations have been found in the a-synuclein gene that cause misfolding of a-synuclein protein. Misfolded protein sticks together to form large cellular structures called Lewy bodies, leading to cell death and Parkinson's.

The same process of DNA encoding proteins via RNA that occurs in humans also occurs in flies (indeed in all living things). This makes it possible to transplant a mutant form of the human a-synuclein gene into flies to trick fly cells into making mutant a-synuclein protein. This causes the formation of Lewy bodies, loss of nerve cells and Parkinson-like motor impairment in flies. Interestingly, also producing normal human Rab11 protein (involved in moving proteins to the cell surface) in these Parkinson's flies dismantles the Lewy bodies, prevents nerve cell death and reverses some Parkinson’s symptoms.

2. dj1

Mitochondria are structures within cells. They are the power plants that produce all the energy needed by the cell. A toxic by-product of energy manufacture is "reactive oxidative species" (ROS), a chemical that can harm the cell. Nerve cells of the substantia nigra, which are lost in Parkinson's, require lots of energy; therefore they produce lots of ROS and are under "stress" to get rid of them before they damage the cell. Damaged cells trigger apoptosis (or “programmed cell death” where cells sacrifice themselves for the greater good) and die. A gene, dj1, helps the cell to clean up ROS. Perhaps unsurprisingly, mutations in dj1 have been found in Parkinson's sufferers; loss of dj1 function results in excessive ROS-induced cell damage, apoptosis and cell death. 

Gretchen Amphlet Parkinson's UK lecture 2013 - Part 2

For Part 1: http://dialoguewithdisability.blogspot.co.uk/2013/04/gretchen-amphlet-parkinsons-uk-lecture.html

Inheritance

Genes, and their mutations, are passed from generation to generation. The classic example of inheritance is eye colour. Eye colour is determined by two different mutant versions of the same gene: a dominant brown eye version (B) and a recessive blue eye version (b). Since we inherit two copies of each gene the combinations BB and Bb will result in brown eyes and only bb will give blue eyes (the B gene is dominant over b). Bb individuals are said to “carry” the b gene even though its affect is masked by the dominant B gene. The way to tell if a trait is dominant is to see if it is present in each generation; if recessive it tends to skip a generation.

Inheriting mutations in Parkinson’s genes

Parkinson’s disease has been observed in multiple members of the same family. When sufferers’ DNA was compared to DNA from non-suffering family members (the sequence of DNA subunits can be read) mutations that only occurred in sufferers were found. These mutations will, via mutant RNA, result in the manufacture of faulty protein that disrupts the normal function of the cell.

By studying such families about 19 “Parkinson’s genes” have been found (both dominant and recessive) and these genes so far account for about 10% of all cases of the disease in the general population.

What about the other 90% of sufferers? Do you carry mutations in these or other Parkinson’s genes? We are all mutants; we carry many mutations in our DNA. However, these changes can have a range of affects, from no impact on protein function to subtle or devastating affects that impact the function on the cell. In one study, sufferers without affected relatives showed more subtle changes in their Parkinson’s genes, causing less obvious changes in protein function. If you inherit two recessive mutations or one dominant mutation you are likely (~100%) to develop Parkinson's whereas these subtle mutations increase the risk only by about 3%.

The genetics of Parkinson’s is likely to be complex, involving many subtle mutations interacting with environmental factors to cause loss of nerve cells; we have only just begun to understand how Parkinson’s is inherited. It is crucial we succeed; understanding the underlying genetics is the only hope we have of developing new treatment to counteract the faulty proteins and prevent the loss of nerve cells.