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Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle

From the Center for Genetic Medicine (Drs. Molon, Di Giovanni, Chen, and Hoffman), Children’s National Medical Center, Washington, DC; Exercise Science (Dr. Clarkson), University of Massachusetts, Amherst; and Department of Neurological & Psychiatric Sciences (Drs. Angelini and Pegoraro), University of Padova, Italy.

Address correspondence and reprint requests to Dr. Eric P. Hoffman, Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010; e-mail: ehoffman{at}cnmcresearch.org

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.

Received August 29, 2003. Accepted in final form December 11, 2003.

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