The University of Alabama

Reprogrammed Protein Shows Neurologic Disease Treatment Promise, UA Research Shows

TUSCALOOSA, Ala. — When reprogrammed in a laboratory, a protein naturally found only in single-cell organisms can correct within animal models a hallmark trait associated with multiple neurodegenerative diseases, according to a paper co-authored by University of Alabama researchers and publishing in the Jan. 16 edition of the journal Cell.

The work done in laboratories at the University of Pennsylvania and UA shows that variants of a chaperone protein, called Hsp 104, may be “highly promising” for eventually halting the progression of diseases such as Parkinson’s and ALS, or amyotrophic lateral sclerosis, according to the scientific article. The research was done in yeast and the tiny nematode C. elegans, models frequently used in research laboratories.

“We have engineered a yeast protein to essentially improve upon its natural activity and to function better in more complex biological systems,” said Dr. Guy Caldwell, UA professor of biological sciences and one of the University’s three co-authors of the journal article.

Chaperone proteins regulate activities associated with protein folding. Proteins must fold properly within cells to function correctly. One misfolding can lead to others and, subsequently, to aggregation, or clumping. In patients with neurodegenerative disease, this aggregation leads to neuron malfunction or cell death.

UA scientists collaborated with researchers from the lab of Dr. James Shorter, at the University of Pennsylvania. UA’s lead contributor is Bryan Martinez, a third-year doctoral student and a 2010 UA graduate. Dr. Kim Caldwell, UA professor of biological sciences, is a co-author. The paper’s lead author is Dr. Meredith E. Jackrel, of the University of Pennsylvania.

Discovering that variants of this protein show such capabilities when placed in metazoans, or multi-cellular organisms, was surprising, Guy Caldwell said. The typical form of the Hsp 104 protein as it naturally occurs — what scientists call the wild type — has been well-studied. And, its ability to return aggregate proteins to their normal state was well-known.

However, multi-cellular organisms do not have an equivalent protein, known as a homolog, within them, and the wild-type form of Hsp 104 was previously shown unable to significantly reduce misfolded protein toxicity in a multi-cellular organism.

Within the UA lab, reprogrammed protein variants, engineered in yeast by the University of Pennsylvania lab, rescued neuron loss associated with the human protein alpha-synuclein. Scientists have learned that people with too many copies of the code for alpha-synuclein within their DNA will contract Parkinson’s.

Extra copies of alpha-synuclein can lead to repeated protein misfolding and the death of the dopamine-producing neurons in the brain. In Parkinson’s patients, the death of these neurons leads to rigid and tremoring limbs, difficulty in movement and impaired reflexes.

In the yeast models, the Hsp 104 variants positively impacted two other types of protein misfolding associated with ALS, often called Lou Gehrig’s disease. This, researchers said, illustrates a broader spectrum of possible disease targets for future treatment.

UA’s portion of the research was funded by the National Science Foundation and the National Institutes of Health.

UA’s department of biological sciences is part of the College of Arts and Sciences, the University’s largest division and the largest liberal arts college in the state. Students from the College have won numerous national awards including Rhodes Scholarships, Goldwater Scholarships and memberships on the USA Today Academic All American Team.

The University of Alabama, a student-centered research university, is experiencing significant growth in both enrollment and academic quality. This growth, which is positively impacting the campus and the state's economy, is in keeping with UA's vision to be the university of choice for the best and brightest students. UA, the state's flagship university, is an academic community united in its commitment to enhancing the quality of life for all Alabamians.