RESEARCH: Spastin disrupts microtubule pathways in muscle

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Large-scale disruption of microtubule pathways in

morphologically normal human spastin muscle.

Molon A, Di Giovanni S, Chen YW, son PM, Angelini

C, Pegoraro E, Hoffman EP.

Center for Genetic Medicine, Children's National

Medical Center, Washington, DC 20010, USA.

OBJECTIVE: To investigate the molecular pathways

disrupted by dominant spastin mutations in apparently

unaffected skeletal muscle from patients with motor

neuron disease (SPG4). METHODS: The authors studied

muscle of three individuals from two unrelated

families affected by spastic paraplegia caused by

spastin mutations. The authors compared RNA expression

profiles to 7 normal and 13 pathologic muscle U95A

profiles (Duchenne dystrophy, acute quadriplegic

myopathy, and spinal muscular atrophy). Data were

validated with U133A arrays with seven different

control specimens. mRNA and protein confirmations were

done for a subset of genes. RESULTS: Both nonsense and

missense mutations in the spastin gene disrupted

microtubule pathways in nonpathologic tissue,

including microtubule dynamics, stability, exocytosis,

and endocytosis. CONCLUSIONS: Normal muscle can be

used to uncover biochemical perturbation in motor

neuron disease. Altered microtubule metabolism in

SPG4-linked hereditary spastic paraplegia patients

leads to pathology of the long descending tracks of

motor neurons that likely have a stringent need for

efficient microtubular transport. As many inherited

neurologic conditions show a systemic biochemical

defect with disease limited to neurons, our data have

broader implications for biochemical pathway studies

of many neurologic disorders.

SOURCE: Neurology. 2004 Apr 13;62(7):1097-104.

http://www.neurology.org/cgi/content/abstract/62/7/1097