MOCA was originally discovered in a screen for presenilin-binding proteins and is entangled with tau in the AD brain (Kashiwa et al., 2000; Chen et al., 2001). Its expression is limited to neurons and testes, and it appears to direct nascent APP to the proteasome for destruction (Chen et al., 2002). MOCA is a guanine exchange factor for Rac1, which interacts with cofilin, LIM kinase, and p21-activated kinase (Pak) to regulate the actin cytoskeleton. Loss of PAK has been linked to synaptic deficits and the protein is reduced in the brain of AD patients (see ARF related news story). MOCA also interacts with N-cadherin to control cell-cell and cell-substrate adhesion (Chen et al., 2005).

MOCA itself has not been genetically linked to any neurodegenerative diseases, although one study found an unconfirmed connection between the MOCA gene and attention deficit hyperactivity disorder (de Silva et al., 2003).

Chen’s MOCA knockout mice lived a normal lifespan and reproduced, but began showing neurological symptoms at about two months of age. The animals suffered limb weakness and ataxia causing difficulty walking and swimming, which suggests problems with sensory or motor systems. Rotarod tests confirmed the phenotype, with homozygous knockout mice lasting an average 31 seconds on the spinning rod, compared to 65 seconds for control animals.

Upon closer examination of the mice, Chen discovered abnormal axonal aggregation of neurofilament protein, primarily in the spinal cord, but also in the cerebellum and brainstem, of the MOCA knockout animals. Using electron microscopy, Chen confirmed clear signals of axonal dystrophy. The axons swelled with mislocalized organelles, vesicles, and autophagic vacuoles. The actin cytoskeleton also appeared disorganized or disassembled, likely due to increased cofilin activity in the knockout animals.

Not surprisingly, the disabled axons showed impaired transport. Knockout mouse motor neurons took up less tracer material injected into the muscles than did neurons in control animals, suggesting impaired retrograde transport. Ligation experiments on the sciatic nerve also showed that anterograde APP trafficking was slowed.

Contrary to the scientists’ hopes, the animals showed no evidence of AD-like plaques. The sequence of mouse APP is different from the human gene, Chen said, so it may not be able to form plaques. However, the researchers suggest that their model has applications for a broad range of conditions.

“Axon dysfunction occurs in many different neurological diseases,” Chen said, such as Alzheimer’s, Huntington’s, and amyotrophic lateral sclerosis. Using the MOCA knockout, the authors said, could allow scientists to tease apart the steps in age-dependent axon degeneration.

“The presence of dystrophic neuritis, axonal swelling, aberrant cytoskeleton, and accumulation of autophagic vacuoles have been well documented in AD brains, but the cellular mechanisms are not clear” wrote Sanjay Pimplikar of the Cleveland Clinic Foundation in Ohio, in an e-mail to ARF. However, he noted that because the MOCA knockouts had fairly normal cortex and limbic systems, and their memory status is unknown, it is too early to make a close connection to Alzheimer’s. “Nevertheless, MOCA is known to interact with presenilins and it is still possible that somewhere in these observations lies a clue to the pathological features observed in AD brains.”—Amber Dance.

Reference:
Chen Q, Peto CA, Shelton DG, Mizisin A, Sawchenko PE, Schubert D. Loss of Modifier of Cell Adhesion Reveals a Pathway Leading to Axonal Degeneration. J. Neurosci. 2009 January 29(1):118-130. Abstract