Proteomics

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Proteomics

Postby dignan » Thu Jul 06, 2006 4:22 pm

Interesting article from the economist that isn't specifically about MS, but about neurodegenerative diseases in general.



From The Economist:

July 6, 2006 -- After the genome, the proteome! That was the cry when the scientific bigwigs running the Human Genome Project were asked what came next. Proteomics—identifying the structure and abundance of all of the proteins in an organism, as genomics sought to identify all of the genes—is a harder and more open-ended task. But, in the end, it is proteins, not genes, that do the actual work in a cell. It is therefore the failure of proteins that actually causes disease, whether that failure is the result of design faults that have been introduced by mutant genes or is just damage from wear and tear.

The genome project thrived on big egos. By contrast, those studying the proteome have been self-effacing, which is why the news is not full of their antics. But although proteomicists have been quiet, they have not been idle, and their results are now starting to appear in scientific journals. This week, for example, saw the publication in Biochemistry of a proteomic study that goes a long way towards establishing a common underlying cause for neurodegenerative diseases such as Parkinson's and Alzheimer's.

It has been known for some time that these conditions involve the accumulation of damaged and misfolded proteins, but what causes that malformation is the subject of debate. Colette Sacksteder, of Pacific Northwest National Laboratory in Richland, in the state of Washington, and her colleagues used proteomic techniques to confirm that a process called nitration is at least part of the cause.

Nitration is one of a range of damaging chemical processes that are lumped together as “oxidative stress”. It has been linked to cellular ageing and cardiovascular disease, and a connection between oxidative stress in general and neurodegenerative disease in particular has been suspected for a long time. To investigate this in more detail, Dr Sacksteder and her team decided to search for all the brain proteins that are susceptible to nitration—though they used mouse brains rather than human ones as their raw material.

This was a huge task. There are more sorts of protein in the brain than in any other bodily organ, though nobody knows exactly how many. Some catalogues already exist, but Dr Sacksteder decided to start from scratch and build a new one.

To do so, she and her colleagues first broke down all the proteins of samples taken from healthy mouse brains into smaller units called peptides. A peptide is a short chain of the amino-acid molecules that are the ultimate components of proteins. By sorting these peptides according to characteristics such as their electric charge and their attraction to water, and then separating them by their molecular weights in machines called mass spectrometers, the team was able to work out the exact composition of each peptide.

Fitting the peptides back into their original proteins is a task that requires a lot of computing power, but when they had finished, the researchers reckoned that they had identified almost 8,000 proteins—the largest catalogue of mammal-brain proteins yet compiled. Mass spectroscopy is so sensitive, though, that it can tell the difference between a nitrated and an un-nitrated peptide. As a result, the team was able to recognise 29 proteins that came in both nitrated and un-nitrated forms. When the scientists looked at the relevant databases they found that more than half of those proteins had been implicated in one or more neurodegenerative diseases.

Following this lead, they decided to investigate the role of nitration in one disease, Parkinson's, in more detail. They injected another group of mice with MPTP, a molecule that simulates the effects of Parkinson's disease. They then measured the relative levels and patterns of nitration in the 29 “candidate” proteins and found significant increases in six of them.

Whether this work will lead to clinical benefits remains to be seen. But it is an impressive demonstration of the power of proteomics. Traditional one-protein-at-a-time methods had uncovered only half a dozen brain proteins susceptible to nitration. A single study has multiplied that number by five, and may have uncovered a general mechanism by which the brain deteriorates.
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