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Altered Axonal Actin Dynamics in Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

Weekly Seminar | Not Open to the Public
Who Should Attend: 


Loss of motor endplates, axonal degeneration and cell death are characteristic pathological features of motoneuron diseases. Distinct gene defects in familial amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) point to different pathophysiological pathways in these two forms of motoneuron disease. These include gain of function mechanisms such as disturbed RNA metabolism and toxicity from dipeptides, but also loss of function of C9ORF72 and SMN that are relevant for synaptic and axonal degeneration. A prominent phenotype of motoneurons from SMA mouse models is reduced axon elongation in the absence of altered motoneuron survival. Smn depletion severely disturbs axonal translocation of a specific subsets of mRNAs. In particular, transcripts associated with axon growth and synaptic activity are reduced, including those coding for α-, ß- and γ-actin. These alterations correlate with disturbed actin dynamics in axons and axon terminals of SMA motoneurons. Similar axonal defects are also observed in C9ORF72 depleted motoneurons. C9ORF72 interacts with cofilin and other actin binding proteins in motoneurons. C9ORF72 loss of function results in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2), acting on downstream small GTPases Arf6 and Rac1 for actin filament dynamic regulation. Thus, common pathological pathways in ALS and SMA exist that could be target for therapy development.

Dr. Michael Sendtner's Figure


Changhe Ji, Jakob Bader, Pradhipa Ramanathan, Luisa Hennlein, Felix Meissner, Sibylle Jablonka, Matthias Mann, Utz Fischer, Michael Sendtner, Michael Briese
Interaction of 7SK with the Smn complex modulates snRNP production
Nat Commun. 2021 Feb 24;12(1):1278. doi: 10.1038/s41467-021-21529-1.
Mehri Moradi, Rajeeve Sivadasan, Lena Saal, Patrick Lüningschrör, Benjamin Dombert, Reena Jagdish Rathod, Daniela C Dieterich, Robert Blum, Michael Sendtner
Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons
J Cell Biol. 2017 Mar 6;216(3):793-814. doi: 10.1083/jcb.201604117. Epub 2017 Feb 28.
Rajeeve Sivadasan, Daniel Hornburg, Carsten Drepper, Nicolas Frank, Sibylle Jablonka, Anna Hansel, Xenia Lojewski, Jared Sterneckert, Andreas Hermann, Pamela J Shaw, Paul G Ince, Matthias Mann, Felix Meissner, Michael Sendtner
C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons
Nat Neurosci. 2016 Dec;19(12):1610-1618. doi: 10.1038/nn.4407. Epub 2016 Oct 10.


Tuesday, October 26, 2021 - 12:30pm


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Darlene White

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