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The Journal of Neuroscience, January 7, 2009, 29(1):118-130; doi:10.1523/JNEUROSCI.3985-08.2009

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Neurobiology of Disease
Loss of Modifier of Cell Adhesion Reveals a Pathway Leading to Axonal Degeneration

Qi Chen,¹ Charles A. Peto,² G. Diane Shelton,³ Andrew Mizisin,³ Paul E. Sawchenko,² and David Schubert¹

¹Cellular Neurobiology Laboratory and ²Neuronal Structure and Function Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, and ³Department of Pathology, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to David Schubert, Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: schubert{at}salk.edu

Axonal dysfunction is the major phenotypic change in many neurodegenerative diseases, but the processes underlying this impairment are not clear. Modifier of cell adhesion (MOCA) is a presenilin binding protein that functions as a guanine nucleotide exchange factor for Rac1. The loss of MOCA in mice leads to axonal degeneration and causes sensorimotor impairments by decreasing cofilin phosphorylation and altering its upstream signaling partners LIM kinase and p21-activated kinase, an enzyme directly downstream of Rac1. The dystrophic axons found in MOCA-deficient mice are associated with abnormal aggregates of neurofilament protein, the disorganization of the axonal cytoskeleton, and the accumulation of autophagic vacuoles and polyubiquitinated proteins. Furthermore, MOCA deficiency causes an alteration in the actin cytoskeleton and the formation of cofilin-containing rod-like structures. The dystrophic axons show functional abnormalities, including impaired axonal transport. These findings demonstrate that MOCA is required for maintaining the functional integrity of axons and define a model for the steps leading to axonal degeneration.

Key words: MOCA; DOCK180; guanine nucleotide exchange factor; axonal degeneration; neurodegeneration; sensorimotor defects

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Received Aug. 20, 2008; revised Nov. 13, 2008; accepted Nov. 27, 2008.

Correspondence should be addressed to David Schubert, Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: schubert{at}salk.edu

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