Getting a Leg Up on Movement Disorders

Over 40 million people worldwide suffer from movement disorders, which are clinically defined as any type of affliction that affects the speed, fluency, ease, or quality of motion. The symptoms of these disorders can manifest in many different ways (the most common being tics, tremors, dystonia, and chorea), and treatment is still elusive for a large number of these often debilitating diseases.  The past several decades, however, have seen enormous advances in our understanding of the genes and proteins underlying these conditions, and what remains to be determined is the way in which these molecules interact with each other to produce either normal or pathological locomotor patterns.

Scaffolding proteins have recently become a point of interest in the field of movement disorders.  As their name implies, these proteins act as “scaffolds” to tether other proteins together, thus facilitating protein-protein interactions.  It has long been thought that scaffolding protein dysfunction could disrupt the formation of protein complexes critical for the production normal locomotion, but evidence for such conjectures has remained elusive.

in a recent article in the journal GENETICS, Dr. Leslie Griffith’s lab at Brandeis University published work implicating one such scaffolding protein of the MAGUK family, known as CASK-b, in locomotor pathology. Using the fruit fly Drosophila melanogaster as a model system, researchers in the lab combined recently-developed genetic tools with cutting-edge computer behavior analysis software to demonstrate that knocking out this protein produces a complex motor deficit (see figure below).  Furthermore, this deficit appears to stem from a loss of CASK-b in the central nervous system, suggesting it plays a role in higher-order regulation of motor output.  Interestingly, both the major locomotor control center of the insect brain (known as the ellipsoid body), as well as the motor neurons which the locomotor control center regulates, do not appear to require this protein to produce normal locomotor patterns.  This finding implies that a novel region or regions of the fly brain may be contributing to central locomotor control.  Understanding both the specific mechanism through which this protein acts, as well as the underlying circuitry responsible for this deficit, could contribute largely to the field of movement disorders as a whole.

Another surprising finding to come out of this study was the discovery of an additional mRNA transcript that arises from an alternative promoter in the CASK locus.  Although similar to CASK-b in many ways, this alternative protein is actually most homologous to another member of the same family in vertebrates, known as MPP1.  MPP1, like most of its MAGUK cousins, is also a scaffolding protein that plays a vital role in bringing various proteins together into signaling complexes, thus providing more opportunities for complex interactions to take place.  The Drosophila genome has many fewer MAGUK proteins than most mammalian genomes.  This finding implies that through utilization of alternative start sites that generate multiple proteins, the fly can still end up with a wide array of subcellular interactions.  It is this underlying diversity of molecular interactions that is thought to allow the fly to produce to a variety of unusually complex behaviors, such as courtship, aggression, flight, and in this case motor control.

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