Smn Depletion Alters Profilin II Expression and Leads to Upregulation of the RhoA/ROCK Pathway and Defects in Neuronal Integrity
Spinal muscular atrophy (SMA) is the most common genetic disease resulting in infant mortality due to severe loss of α-motor neurons. SMA is caused by mutations or deletions of the ubiquitously expressed survival motor neuron (SMN) gene. However, why α-motor neurons of SMA patients are specifically affected is not clear. We demonstrate here that Smn knockdown in PC12 cells alters the expression pattern of profilin II, resulting in an increase in the neuronal-specific profilin IIa isoform. Moreover, the depletion of Smn, a known interacting partner of profilin IIa, further contributes to the increased profilin IIa availability. Altogether, this leads to an increased formation of ROCK/profilin IIa complex and an inappropriate activation of the RhoA/ROCK pathway, resulting in altered cytoskeletal integrity and a subsequent defect in neuritogenesis. This study represents the first description of a mechanism underlying SMA pathogenesis and highlights new targets for therapeutic intervention for this devastating disorder.
KeywordsSpinal muscular atrophy Survival motor neuron Smn knockdown Profilin IIa
Unable to display preview. Download preview PDF.
- Giesemann, T., Rathke-Hartlieb, S., Rothkegel, M., Bartsch, J. W., Buchmeier, S., Jockusch, B. M., et al. (1999). A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with Smn in nuclear gems. Journal of Biological Chemistry, 274(53), 37908–37914.PubMedCrossRefGoogle Scholar
- Lambrechts, A., Braun, A., Jonckheere, V., Aszodi, A., Lanier, L. M., Robbens, J., et al. (2000). Profilin II is alternatively spliced, resulting in profilin isoforms that are differentially expressed and have distinct biochemical properties. Molecular and Cellular Biology, 20(21), 8209–8219.PubMedCrossRefGoogle Scholar
- Negishi, M., & Katoh, H. (2002). Rho family GTPases as key regulators for neuronal network formation. Journal of Biochemistry (Tokyo), 132(2), 157–166.Google Scholar
- Nusser, N., Gosmanova, E., Zheng, Y., & Tigyi, G. (2002). Nerve growth factor signals through TrkA, phosphatidylinositol 3-kinase, and Rac1 to inactivate RhoA during the initiation of neuronal differentiation of PC12 cells. Journal of Biological Chemistry, 277(39), 35840–35846.PubMedCrossRefGoogle Scholar
- Rossoll, W., Jablonka, S., Andreassi, C., Kroning, A. K., Karle, K., Monani, U. R., et al. (2003). Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. Journal of Cell Biology, 163(4), 801–812.PubMedCrossRefGoogle Scholar
- Rossoll, W., Kroning, A. K., Ohndorf, U. M., Steegborn, C., Jablonka, S., & Sendtner, M. (2002). Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: A role for Smn in RNA processing in motor axons? Human Molecular Genetics, 11(1), 93–105.PubMedCrossRefGoogle Scholar
- Sharma, A., Lambrechts, A., Hao, le T., Le, T. T., Sewry, C. A., Ampe, C., et al. (2005). A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells. Experimental Cell Research, 309(1), 185–197.PubMedCrossRefGoogle Scholar