[olsen]

(I think the information in this aritcle relates to another discussion, but cannot remember which one right now..it is old information though felt the statement concerning the toxicity of dopamine and how it is sequestered in the brain was very important. This info came from experiments on PD models. I have a shotgun approach to research--frequently come across stuff I know is relevant to something being discussed--just cannot remember what...madelyn)

http://www.hhmi.org/news/lindquist20060622.html

"...Lindquist and her colleagues had conducted a genetic screen in yeast to discover genes whose activity affected the toxicity of alpha-synuclein. That study showed that genes enhancing ER-to-Golgi trafficking prevented alpha-synuclein toxicity. In particular, they found that one protein, called Ypt1p, which is involved in regulating trafficking could also be switched on to suppress alpha-synuclein toxicity in yeast cells.

“Our findings indicated that this ER-to-Golgi trafficking pathway is intimately coupled to the pathology, although in humans there are likely others involved as well, given how many genes we found that modified alpha-synuclein toxicity,” said Lindquist. “But these findings were so persuasive that we decided we needed to test whether enhancing Ypt1p activity would suppress alpha-synuclein toxicity in animal models of the disease....”

The researchers next studied whether enhancing activity of the mammalian Ytp1p counterpart, called Rab1, suppressed alpha-synuclein toxicity in the fruitfly Drosophila, the roundworm C. elegans and in cultures of rat neurons. ..

“They all came back with the same answer,” said Lindquist. “All saw significant suppression of toxicity; although none saw complete suppression, which confirms our yeast studies showing that other pathways are affected by alpha-synuclein accumulation. However, importantly, the results of our genetic screen have given us a way to ask important questions about these other aspects of alpha-synuclein toxicity,” she said.

Lindquist also said the findings give important clues to why dopamine-producing neurons in the brain are the most vulnerable neurons to toxic alpha-synuclein accumulation. The death of such neurons reduces brain dopamine levels, causing the tremors and other symptoms of Parkinson's disease. Dopamine is one of many types of neurotransmitter -- chemical signals that one neuron launches at its neighbor to trigger a nerve impulse.

"OF ALL THE NEUROTRANSMITTERS, DOPAMINE HAS A HIGHER POTENTIAL FOR BEING TOXIC,' SHE SAID. "ITS TOXICITY IS NORMALLY PREVENTED IN THE NEURON BY SEQUESTRATION WITHIN VESICLES FOR TRANSPORT FROM THE ER. BUT A DEFECT IN ER TRAFFICKING CAUSED BY ALPHA-SYNUCLEIN ACCUMULATION COULD CAUSE THE TOXIC BUILDUP OF DOPAMINE TO OCCUR IN THESE NEURONS."

Lindquist and her colleagues believe their findings will guide the search for new drugs that suppress alpha-synuclein toxicity by enhancing the machinery of ER-to-Golgi transport...


emove had an article about this report:http://www.mdvu.org/emove/article.asp?ID=893
Blockade of vesicle traffic between the ER and Golgi ...earliest detectable pathological event from overexpression of both normal and mutant alpha-synuclein...

Normal and mutant AS were over-expressed in yeast using an inducible promoter. Results showed:

--A slight decline in viability ... apparent within 4 hours, and 60% of cells lost colony-forming ability by 8 hours.

--Endoplasmic reticulum stress, as measured by the unfolded protein response, was detectable by 6 hours. Proteasome activity at this time was normal, suggesting that proteasome dysfunction is a downstream event, not a primary cause, of AS-induced cell dysfunction.

--Alpha-synuclein impaired the proteasome degradation of CPY* and alkaline phosphatase, which require trafficking from the ER to the Golgi, but not degradation of Sec61-2p, which does not...

--Genetic screening for suppressors and enhancers of AS toxicity identified Ypt1p as one of the most potent toxicity suppressors. Ypt1p is a Rab GTPase which promotes ER-to-Golgi transport by promoting docking of vesicles to the Golgi. Ypt1p overexpression rescued AS-induced toxicity in yeast cells, while expression of a negative regulator of Ytp1p increased AS toxicity.

--Overexpression of Rab1, the Drosophila form of Ytp1p, fully suppressed AS-induced toxicity in dopaminergic neurons in both flies and C. elegans.

--Overexpression of transduced Rab1 in rat... neurons almost completely protected dopaminergic cells from A53T mutant AS overexpression.

“... ability of Rab1 to protect against AS-induced neuronal loss in three independent animal models is strong evidence for a specific link between AS and ER-Golgi trafficking,” the authors conclude.

A related article noted:
http://www.mdvu.org/emove/article.asp?ID=853