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Rare, Lethal Childhood Disease Tracked to Specific Protein

Working in the lab of Robert Goldman, PhD, chair of cell and molecular biology, postdoctoral fellow Saleemulla Mahammad, PhD, helped identify the role gigaxonin, the defective protein pictured above, plays in the development of a rare and untreatable genetic disease in children.

For the first time, a defective protein that plays a specific role in degrading intermediate filaments (IF), one of three classes of filaments that form the structure of nerve cells, has been discovered by an international team of researchers. The protein, gigaxonin, was first identified in children with a rare and untreatable genetic disease known as giant axonal neuropathy (GAN). 

The knowledge of gigaxonin's specific role explains why a failure of the protein to deteriorate would lead to massive accumulation of IF in the neuronal cells of GAN children, said postdoctoral fellow Saleemulla Mahammad, PhD, who works in the laboratory of Robert Goldman, PhD, chair of cell and molecular biology

Mahammad collaborated with Puneet Opal, MD, PhD, associate Professor in the Ken and Ruth Davee Department of Neurology and cell and molecular biology, along with researchers at INSERM in Montpelier, France, and the Université Laval in Quebec, Canada, on the project. 

When the researchers introduced gigaxonin into both control and patient samples, the results were dramatic. In cells cultured from GAN patients, the complex network of filaments disappeared. The filaments in the control cells also disappeared following overexpression of the gigaxonin protein. 

These findings indicate that gigaxonin plays a critical role in regulating the turnover of IF proteins. When gigaxonin is defective, filaments pile up, and eventually the accumulation disrupts the normal functioning of nerve cells, leading to diseases such as GAN. 

Gigaxonin is the first factor identified that plays a specific role in the degradation of several types of IF proteins, including neurofilaments, according to Mahammad. This discovery may have implications for more common types of neurodegenerative diseases that are also characterized by large accumulations of IF proteins, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Charcot-Marie-Tooth (CMT) disease, neuronal intermediate filament inclusion disease (NIFID), and diabetic neuropathy. 

GAN is an extremely rare genetic disorder that strikes at both the peripheral and central nervous systems of children. The leading GAN disease foundation, Hannah's Hope Fund, currently knows of 31 cases worldwide, 19 in the United States. There are no symptoms at birth, but by age three the first signs of muscle weakness usually appear and progress slowly but steadily. With increasing difficulty in walking and coordinating hand movements, children with GAN are often wheelchair-bound by age 10. Over time, they become dependent on feeding and breathing tubes. Few will survive into young adulthood. The pathological markers for GAN are swollen (“giant”) axons, filled with abnormal aggregates of neurofilaments, rich in Ifs. 

Mahammad presented this research at the American Society for Cell Biology Annual Meeting in December. It was supported by NIH grant 1P01GM096971-01 and Hannah's Hope Fund. 

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