Disorders A - Z:   A    B   C    D    E    F    G    H    I    J    K    L    M    N    O    P    Q    R    S    T    U    V    W    X    Y    Z

Skip secondary menu

Organized Protein Network Discovered in the Ataxias


For release: Monday, August 14, 2006

Scientists have recently announced discovery of a sophisticated network of interacting proteins that forms the basis for inherited neurodegenerative diseases such as the ataxias.  This network gives scientists new insight into the normal function of disease-related genes.  It also provides possible candidate sites for targeted therapies aimed at the ataxias and other progressive neurological disorders.

The research, funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), featured a proteomic mapping tool called an interactome, which is designed to measure molecular interactions within cells.  The interactome identified a vast collection of interactions among ataxia-related proteins and between these proteins and other genetic material inside a cell.  Findings appear in the journal Cell.*

Proteins serve as building blocks inside the body’s cells, tissues, and organs.  They also send and receive electrical signals from other cells and direct chemical reactions that govern cellular and bodily functions including movement and metabolism.  Each protein has its own unique function.  Organs and systems throughout the body can be severely affected when certain proteins malfunction or are not produced in sufficient quantities.

Lead scientist Huda Y. Zoghbi, M.D., Baylor College of Medicine, and colleagues designed the interactome to identify and map common links among protein connections that led to the death of Purkinje cells—nerve cells found in the brain’s cerebellar cortex that control motor coordination.  Purkinje cell death causes motor impairment and progressive ataxia (lack of muscle control and coordination).  The loss of these cells is a noted feature in the inherited human ataxias and in several animal models of ataxia.  Purkinje cell death is also seen in other disorders that mistakenly copy and repeat a three-letter genetic code too many times.

“Many of the inherited human ataxias and mouse models share motor features and pathology.  We wanted to know if the proteins that function abnormally in these disorders interact with each other and if such interactions could reveal common functions or molecular pathways that may explain how and why brain cells die in these diseases,” said Dr. Zoghbi.

The researchers (from Baylor College of Medicine, Dana-Farber Center Institute, and University of Notre Dame) screened 54 proteins, 23 of which were known to cause inherited ataxias and an additional 31 that were associated with those proteins.  The proteins were first tested using a yeast-based model to highlight common molecular pathways and identify protein pairing.  They were then screened against much larger, established collections of DNA sequences that code for proteins expressed in the brain.

Results revealed 770 protein-protein interactions involving 42 different ataxia-associated pairs, most of which were discovered for the first time.  While some proteins interacted with only one partner, the interactome showed that several ataxia-associated proteins shared many common partners, in effect forming a “hub” or subset of connections in the larger ataxia network.  Many of these protein links revealed common cellular pathways that might lead to Purkinje cell dysfunction and degeneration.  Such common links may help scientists understand similarities among several of the inherited ataxias or related neurodegenerative disorders.

The ataxia protein interactome can now be used to identify biomarkers or functional links for a variety of disorders that may be caused by more than one gene and share common interacting proteins and environmental influences.  The interactome also has the potential to highlight candidate genes for targeted drug therapy aimed at restoring normal cellular function.

*Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual J-F, Fisk CJ, Li N, Smolyar A, Hill DE, Barabasi A-L, Vidal M, Zoghbi HY.  “A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell deterioration.”  Cell, May 19, 2006; 125(4), pp. 801-814.

-by Paul Girolami, NINDS Office of Communications and Public Liaison

Last Modified January 31, 2007