2010/09/10

Mutations That Cause Neurodegenerative Disorders

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive neuromuscular disease that weakens and eventually destroys motor neurons (components of the nervous system that connect the brain with the skeletal muscles). 4-8 per 1000,000 people suffer from ALS worldwide, with 5000 new cases occurring in the United States and 900 in Spain each year. In collaborative effort with Juan S. Bonifacino from National Institute of Child Health and Human Development at Bethesda, (USA), Dr. A. Hierro's group from CIC bioGUNE have now determined the three-dimensional structure of the C-terminal fragment of mouse Vps54 protein by using X-ray crystallographic techniques. Their findings represent a key step in elucidatation of the structural basis for the wobbler mouse phenotype, one of the most extensively studied animal models of ALS, and highlight the importance of endosomal/lysosomal traffic for maintenance of motor neuron integrity.

In eukaryotic cells, protein secretion and the transport of materials between membrane-bounded organelles require efficient and accurate delivery of carrier vesicles to their correct destination. Recent studies have revealed a large number of evolutionarily conserved proteins that may function in tethering vesicles to their target membrane in preparation for subsequent docking and fusion. Among these is the multisubunit Golgi-associated retrograde protein (GARP) complex, which is required for tethering and fusion of endosome-derived transport vesicles to the trans-Golgi network. GARP is a heterotrimeric complex composed of Vps51, Vps52, Vps53 and Vps54 subunits. Mutation of leucine-967 to glutamine in Vps54 is responsible for the wobbler mouse phenotype, characterized by spinal muscular atrophy (SMA) and defective spermiogenesis. The similarities in motor neuron degeneration in the wobbler model and ALS patients raise the possibility of common pathways to cell death, including impaired vesicle traffic.

The three-dimensional structure of Vps54 reveals that residue Leucine-967 is completely buried within a groove formed by a -helical bundle through predominantly hydrophobic interactions. Both the hydrophobicity and size of the Leu967 side chain are critical for protein stability and folding in vitro. More interestingly, Dr. Hierro's group has also demonstrated that the L967Q Vps54 mutant has a reduced solubility and stability when compared with the wild type protein, which results in a shortened half-life. Thus, the phenotype of wobbler mice is caused by destabilization of Vps54 and consequently reduced levels of the entire GARP complex.

Alfonso Martínez de la Cruz

Proc Natl Acad Sci U S A. 2010 Jul 20; 107(29):12860-5.