new protein research in neuron malfunction

[Guest guest]

I am thinking perhaps this could benefit those of us with CMT too. ~ G

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Protein Linked to Movement Disorders from Institute,

February 1, 2003

February 1, 2003— Using a tiny worm to model a severe childhood movement

disorder,

researchers at The University of Alabama have discovered the role of a

protein that may have implications for a number of neurological

syndromes

such as Parkinson's and Huntington's diseases.

With support from grants from the Medical Institute and

the Dystonia Medical Research Foundation, the scientists found that a

mutated gene associated with early onset dystonia, a severe hereditary

movement disorder, normally helps manage protein folding.

The mutated gene, TOR1A (or DYT1), was linked to the disorder in 1997,

but the role

of its protein, torsinA, had been unknown until this finding, reported

in the cover

article of the February 1, 2003, issue of Human Molecular Genetics.

" We believe that torsinA and the family of torsin proteins are normally

neuroprotective, used by cells as a quality control mechanism to clear

proteins that have misfolded, " said the lead author of the article, Guy

Caldwell, assistant professor of biological sciences.

" When torsin's protective mechanism goes awry, it results in protein

aggregation, which could be a cause of neuron malfunction, " he said.

Caldwell and colleagues were able to provide the first molecular

explanation of torsinA's function by using the microscopic nematode

roundworm Caenorhabditis elegans (C. elegans), an animal model that has

aided in deciphering cellular functions for genes involved in neuronal

functioning. Almost half of all human hereditary diseases, including

dystonia and Parkinson's disease, have been linked to genetic components

also found in C elegans, according to Caldwell.

While early onset dystonia is rare and characterized by twisting

contortions, muscle

contractions, or abnormal postures that begin in childhood, dystonia

diseases are

the third most common movement disorders.

" Dystonia is possibly a consequence of the inability of neurons to

properly respond to

environmental or physiological stress-induced changes in protein

structure, "

Caldwell said. " Specific changes in torsin activity may render cells

more susceptible to such stresses. "

These findings further suggest that malfunctioning torsin proteins may

play a role in a number of diseases that feature abnormal aggregations

of protein. For example, torsin has been found in protein clumps known

as Lewy bodies in the brains of patients with Parkinson's disease,

Caldwell said.

" Failure of proteins to adopt their proper structure is a common cause

of neuronal

dysfunction, and many diseases of the nervous system involve aggregates,

or clumps, of protein forming in cells, " he explained.

The researchers transplanted the green fluorescent protein (GFP) that

causes

jellyfish to glow into C elegans and induced it to form misfolded

protein aggregates.

Introducing functioning torsinA into the worm significantly reduced the

fluorescent

protein clumps, whereas worms genetically altered to produce a mutated

form of torsin

similar to that associated with dystonia were unable to suppress the

formation of protein clumps. " Torsin activity appears to be conserved

across species, from humans to worms, " Caldwell said.

This successful experimental technique opens the door to a number of

new

investigative avenues, the scientists say. Their lab has already

genetically engineered a fusion between GFP and a human protein,

alpha-synuclein, implicated in Parkinson's disease, and early findings

show " torsins are equally effective in suppressing alpha-synuclein

aggregation in worms, " Caldwell said.

The work also raises the question of whether torsins might be useful as

a therapeutic drug to prevent protein clumping, the researchers say.

" There is a potential for torsins as molecules that serve a more general

neuroprotective function in preventing

misfolding of proteins within cells, " Caldwell said. " They may have

promise as a novel

class of therapeutics for diseases in which misfolded protein aggregates

are suspected

to be a causative factor, such as Parkinson's, Alzheimer's,

spinocerebellar ataxias, and Huntington's. & rdquo;

The study's co-authors are all members of Caldwell's lab. They include

Kim Caldwell,

Songsong Cao, Elaina Sexton, Gelwix, and Bevel.

The lab

recently was named one of 11 worldwide to receive a research grant from

the J.

Fox Foundation for Parkinson's Research.

Contact: Fox

Aisen, aisenc@..., (317)843-2276

©2003 Medical Institute

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