Striatum and the neurophysiology of movement

Neuroscience research related to the striatum and basal ganglia.

Thursday, September 28, 2006

Traffic issues

There is a new airport in Bangkok and it will be served by new taxis. Some of us will miss those old taxis that charged only 200 ฿ for a trip to the airport. I wonder whether passengers will accumulate at the Victory Monument Station waiting for cheaper forms of transportation.

Alpha-synuclein is a molecule involved in Parkinson's disease. Mutation in this molecule cause degeneration of dopaminergic neurones similar to that seen in patients. We ignore both the normal function of α-synuclein, and how it causes cell death. Although it is know that α-synuclein must be attached to membranes to cause neurodegeneration. Some answers come in a recent study by Cooper and coworkers published in Science (2006). They study the α-synuclein in Yeast (Saccharomyces cerevisiae) --Yes you are right. Yeast neither have striatum nor get Parkinson's disease. But, yeast has the advantage that can grow quickly, and can be mutated easily. So, Cooper and co-workers added extra α-Syn gene to Yeast. When two copies of the gene were added cells did not grow very well and died. The author noticed an increase in the unfolded-protein response (UPR) and concluded that death was due to increase in misfolded proteins.

Normally in a cell protein that are misfolded become degraded. To see which degradation pathway was altered, they chose two misfolded proteins (CPY*, sec61-2p) and follow their degradation pathway. Of these two, CPY* is soluble misfolded, and sec61-2p is bound to membranes, and they are degraded differently. Of these two, only the degradation of the soluble misfolded protein (i.e. CPY*) was affected. So they concluded that a-synuclein somehow impairs the vesicle trafficking. If this is true, one should expect that yeast overexpressing α-synuclein should have altered trafficking of soluble proteins (and not membrane -bound ones). And this is exactly what happen in yeast overexpressing α-synuclein: normal CPY gets stack, but not alkaline phosphatase (membrane-bound protein).

So far so good. α-synuclein affects membrane trafficking. But how? To answer this question, Cooper and co-workers screened for candidate genes. They have a library of 3000 genes and transfected them (individually) into yeast that have an inducible α-synuclein (the promoter used was under the control of galactose, so by growing the yeast in galactose they can turn the α-synuclein "on"). So by observing which yeast were able to grow in glucose, and still grow in galactose they found the candidate genes for rescue the α-synuclein toxicity.

There were many genes. But an important on was Rab1 (called Ypt1p in yeast). Rab1 is a small GTP-ase needed to the tethering and docking of the vesicle to the Golgi apparatus. So alpha-synuclein may be involved in vesicle trafficking. Expression of Rab1 rescue the toxic effects due to to much α-synuclein.

But the question still there: Why the dopaminergic neurones are affected. Cooper proposes that the problem is the vesicular monoamine transported 2 (VMAT2). If the secretory pathway is not working, there is not proper delivery of VMAT2, and dopamine starts to accumulate in the cytosol. Dopamine is chemically unstable, and without being promptly packer would become oxidised, generates reactive-oxygen species and causes cell damage.