Disease-causing protein protects against nerve damage in Parkinson's disease



DALLAS - Nov. 3, 2005 - Researchers at UT Southwestern Medical Center have 
discovered that a protein associated with causing neurodegenerative 
conditions may, when appearing in normal amounts, actually protect against 
neurodegeneration.
 
 The findings, appearing in today's issue of the journal Cell, have surprised 
the researchers, because an excess of the same specific protein - 
alpha-synuclein - causes Parkinson's disease.
 
 "It's the first time that anyone has shown that synuclein has any positive 
function at all in the body, and this is important because it's been known to 
be involved in neurodegeneration," said Dr. Thomas Südhof, senior author of 
the study and director of the Center for Basic Neuroscience. Dr. Südhof also 
is an investigator in the Howard Hughes Medical Institute.

 


Dr. Thomas Südhof, director of the Center for Basic Neuroscience, is senior 
investigator of a study which showed that a protein associated with causing 
neurodegenerative conditions may, when appearing in normal amounts, actually 
protect against neurodegeneration. The findings are surprising, because an 
excess of the same specific protein causes Parkinson’s disease. 
 

The key to their findings was determining the interaction between 
alpha-synuclein and another protein - cysteine-string-protein-alpha, or 
CSP-alpha. The researchers' investigation involved several strains of mutant 
mice, which produced differing amounts of CSP-alpha or alpha-synuclein.
 
 CSP-alpha is a "co-chaperone," meaning that it helps other proteins fold into 
their normal shapes, a vital process in the instantaneous reactions that 
occur at terminals of a nerve cell. When mutant mice lack only CSP-alpha, 
they appear normal for their first three weeks, then undergo rapid nerve 
degeneration and die at one to four months of age.
 
 When mutant mice lack only alpha-synuclein, on the other hand, they continue 
to appear normal as they age, indicating that alpha-synuclein might not be 
essential in healthy nerve cells.
 
 But mice that have been bred to produce an excess of human alpha-synuclein 
undergo a slowly progressing nerve degeneration resembling Parkinson's.
 
 The researchers bred mice lacking CSP with mice with excessive human 
synuclein in their brains, expecting to see a faster descent into the 
Parkinson's-like symptoms in the offspring. Instead, they produced apparently 
healthy animals. In their terms, the alpha-synuclein "rescued" the mice from 
the harmful effects of lacking CSP-alpha.
 
 The results were "exactly the opposite of what I expected," said Dr. 
Sreeganga Chandra, instructor in the Center for Basic Neuroscience and lead 
author of the study. "The rescued animals can live for one year or longer."
 
 The researchers also bred mice that produced neither CSP-alpha nor 
alpha-synuclein and found they suffered neurodegeneration faster than mice 
just lacking CSP-alpha - another sign that alpha-synuclein protects against a 
lack of CSP-alpha.
 
 In humans, clumps of alpha-synuclein, called Lewy bodies, are found in the 
brain cells of patients with Parkinson's, Alzheimer's and other degenerative 
diseases. The researchers speculate that the formation of Lewy bodies may 
take alpha-synuclein out of circulation in cells, thus removing its 
protective action.
 
 Testing this hypothesis would involve looking for mutations in the genes for 
CSP-alpha or alpha-synuclein in patients with neurodegenerative diseases. 
"Trying to understand what's going on in a dying brain is very difficult," 
said Dr. Südhof, who directs the Gill Center for Research on Brain Cell 
Communication and the C. Vincent Prothro Center for Research in Basic 
Neuroscience.
 
 The researchers also found that alpha-synuclein doesn't bind to or react with 
the same proteins that CSP-alpha does, so it doesn't simply act as a 
substitute. However, both molecules bind to the membranes of synaptic 
vesicles - small spheres that contain the nerve cell's neurotransmitters, 
chemicals that carry signals between brain cells - indicating that they both 
act at the vesicles' surface.
 
 "There's a pathway, but we don't really know all the players in this 
pathway," Dr. Chandra said.
 
 Other researchers involved in the work were Gilbert Gallardo, student 
research assistant at the Center for Basic Neuroscience, and researchers from 
Germany and Spain.
 
 The work was supported in part by the National Institutes of Health, the 
American Parkinson Disease Association and the Spanish Ministry of Education. 

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