A genetic model for hereditary spastic paraplegia (HSP) disease

Hereditary spastic paraplegia (HSP) is a devastating motor disorder that relegates patients to walkers and, in more severe cases, wheelchairs. In work reported this week, researchers have taken our understanding of HSP to a new level with the development of an animal model for the disease. The findings suggest that, in many cases, HSP may result from the improper regulation of microtubules, which make up a large part of a nerve cell's scaffolding. This could explain why the specific nerve cells that are preferentially affected in HSP – those that send signals from the brain's cerebral cortex to the motor neurons that initiate muscle contractions – show a progressive dysfunction that culminates in degeneration.

Genetic anomalies in more than 20 different genes have been associated with HSP, but mutations in one gene in particular, SPG4, are responsible for more than 40% of all cases. SPG4 encodes a protein called spastin, which previous research has shown to destabilize microtubules, the tiny hollow protein tubes that originate near the nucleus and extend into the long processes of neurons. Through their interactions with other proteins, microtubules essentially represent the dynamic scaffolding of the nerve cell. In neurons, microtubules' responsibilities include carrying cellular components to distant regions of the cell, regulating the growth of neuronal branches, and providing a substrate for important protein interactions. Microtubules grow and shrink, and their stability at a given time and place can be regulated by other proteins to facilitate specific cellular functions.

The new research, from the laboratories of Dr. Kendal Broadie (Vanderbilt University) and Dr. Andrea Daga (University of Padova, Italy), examines how spastin is involved in neuronal communication. Because the spastin gene is similar in the Drosophila (fruit fly) genetic model and in humans, the protein is predicted to perform the same function in both organisms. Therefore, to study how spastin functions in living neurons, the researchers designed transgenic flies that possess altered amounts of spastin protein in their neurons and assessed the effects. Using this approach, they found that spastin protein localizes to synapses, specialized sites of neuronal communication, where it acts to locally destabilize microtubules. Moreover, the researchers found that specific drugs that alter microtubule stability appear to remedy defects that occur in synaptic function as a result of changes in neuronal spastin levels. All told, the study provides intriguing new insight into how a genetic mutation that alters microtubule function may disrupt the way neurons communicate and offers a new line of thinking about possible treatments for the debilitating HSP condition.

Nick Trotta, Genny Orso, Maria Giovanna Rossetto, Andrea Daga, and Kendal Broadie: "The Hereditary Spastic Paraplegia Gene, spastin, Regulates Microtubule Stability to Modulate Synaptic Structure and Function"

Publishing in Current Biology, Volume 14, Number 13, July 13, 2004, pages 1135-1147.

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