Building a healthy axon, like erecting a skyscraper, takes a variety of workers and materials: the cytoskeletal elements that form the structure, the energy provided by mitochondria, and the participation of other organelles such as the endoplasmic reticulum (see ARF related news story). In a paper posted online by PNAS this week, scientists from the Chinese Academy of Sciences in Shanghai name a new construction worker to the crew. They found that multisynthase complex p43 (MSC p43) is required for the assembly of neurofilaments, which undergird axon stability.

First author Xiaodong Zhu, principal investigator Jiawei Zhou, and colleagues discovered that neurofilament-L interacts with the pro-inflammatory protein MSC p43 in a yeast two-hybrid screen. Overexpression of neurofilament-L caused the formation of MSC p43-positive aggregates. These data led them to characterize MSC p43’s role in neural development and function.

The protein is expressed in several parts of the CNS, including the ventral horn of the spinal cord and the hippocampus. MSC p43-null mice exhibited a variety of symptoms including lameness of the hind limbs and decreased motor activity on a rotarod test. They also had muscular atrophy and decreased innervation of muscle fibers by two months of age. When the scientists examined the axons in the lumbar ventral roots of two-month-old null mutants, they observed shrunken, collapsed structures. The knockout animals also had fewer myelinated axons than did wild-type mice.

Next, the scientists explored the effects of MSC p43 on neurofilament networks. Overexpression of the protein in SH-SYS5 neuroblastoma cells resulted in punctate aggregates containing neurofilaments, suggesting the network was disassembled. Using electron microscopy, Zhu and colleagues found that neurofilaments were disorganized, with fewer and shorter fibrils than normal, in axons from two-month-old MSC p43-null mice. The animals also showed a two- to threefold increase in neurofilament phosphorylation levels compared to wild-type littermates. Experiments with hippocampal neural cultures bore out the role of MSC p43 as a negative regulator of neurofilament phosphorylation. The altered phosphorylation in the null animals appeared to cause the disruption of the neurofilament network.

The authors suggested that the symptoms of the MSC p43-null mice are similar to those of one type of Charcot-Marie-Tooth disease, which also affects peripheral nerves. Mutations in neurofilament-L have been linked to this type 2D CMT (Mersiyanova et al., 2000). Zhou noted that accumulation of hyperphosphorylated neurofilament has been linked to other diseases, such as ALS (Rouleau et al., 1996) and Parkinson disease (Goldman et al., 1983). “It is likely that the dysfunction of MSC p43 may be relevant to neurological disorders besides CMT,” he wrote in an e-mail to ARF.—Amber Dance

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References

News Citations

  1. Of Axons and Root Hairs: Plants in the Neurodegeneration Lab?

Paper Citations

  1. . A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000 Jul;67(1):37-46. PubMed.
  2. . SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. Ann Neurol. 1996 Jan;39(1):128-31. PubMed.
  3. . Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983 Sep 9;221(4615):1082-4. PubMed.

Further Reading

Papers

  1. . Real-time imaging reveals defects of fast axonal transport induced by disorganization of intermediate filaments. FASEB J. 2009 Sep;23(9):3213-25. PubMed.
  2. . Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum Mol Genet. 2008 Feb 1;17(3):367-75. PubMed.
  3. . Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1B mice. Neuron. 2008 Feb 7;57(3):393-405. PubMed.

Primary Papers

  1. . MSC p43 required for axonal development in motor neurons. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15944-9. PubMed.