Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration.
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.
Chen
Qi
Q
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Peto
Charles A
CA
Shelton
G Diane
GD
Mizisin
Andrew
A
Sawchenko
Paul E
PE
Schubert
David
D
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002352:Carrier Proteins; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D020233:Gait Disorders, Neurologic / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D020426:Sciatic Neuropathy; D015398:Signal Transduction / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism; D013266:Stilbamidines / Q000378:metabolism; D025822:Ubiquitin C / Q000378:metabolism
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D051339:Actin Depolymerizing Factors; D002352:Carrier Proteins; C410623:Dock3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D013266:Stilbamidines; D025822:Ubiquitin C; C066858:neurofilament protein NF 68