Notes from Motor Neuron Disease Mechanisms I (Saturday November 12, 2011) at 41st SFN in Washington, DC
Saturday’s session of the 41st annual meeting of the Society of Neuroscience included a nanosymposium on potential molecular mechanisms related to motor neuron disease. The session was chaired by Jordi Magrane, Ph.D. from the Weill Cornell Medical College in New York.
The first speaker was Trisha Stankiewicz from the VA Medical Center in Denver and the University of Denver. According to Stankiewicz, juvenile onset amyotrophic lateral sclerosis, linked to mutations in the ALSIN, or ALS2, which controls Rac signaling and is thought to promote neurite outgrowth. Her work focused on understanding the potential impact of inhibiting Rac signaling to regulate neurotoxicity. Interestingly, her work showed that the neurotoxic effects of Rac may be independent of caspase expression, which has long been reported to play a primary role in neurotoxicity. Stankiewicz’s experiments were done in cerebellar granule neurons. During the discussion following her presentation, Stankiewicz responded that the obvious next steps would be to investigate these findings in primary motor neurons (Stankiewicz, 2011).
3-5% of all cases of ALS have been linked thus far to mutations in the RNA-binding protein FUS which cause the FUS protein to aggregate in the cytoplasm of cells. Ewout Groen, a PhD student from the University Medical Center in Utrecht, Netherlands talked about this relatively newly identified genetic factor in ALS and how this mislocalization may play a role in the development of the disease. He reported that at least 222 different proteins that bind with FUS normally have been identified to date, including at least two other ALS related proteins, TDP43 and ATXN. Using mass spectrometry, he found that FUS binds to SMN proteins which play a critical role in RNA splicing crucial to neuron health and the growth of dendrites and axons. SMN mutations have casually been linked to spinal muscular atrophy. However, looking at the spinal cord collected from an ALS patient, Groen found that the FUS mutation enhanced this interaction in the cytoplasm. In summary, Groen’s work suggests a relationship between the presence of FUS in the cytoplasm and the ability of a cell to conduct RNA splicing efficiently. Groen gave a talk similar to this one during a satellite event focused on RNA-binding proteins the day before he presented it to the Society for Neuroscience (Groen, 2011).
From Christopher Shaw’s lab at Kings College in London, Y. Kim spoke about potential reasons TDP43 and/or FUS mislocalizes into the cytoplasm, which occurs in small subsets of ALS patients. Research on these two disease associated proteins shows that their aggregation and sequestration leading Kim to suggest that this causes a toxic gain of function in the cytoplasm and leads to the degeneration of motor neurons. Whether or not it is a toxic gain or loss of function however remains controversial. Kim used different stressors, one for osmotic stress, Sorbitol, and another for oxidative stress, Arsenite, on cells to see if TDP43 and FUS proteins acted differently in response. The results showed that both FUS and TDP43 are released into the cytoplasm by inducing either stress on these cells. This work adds to the growing understanding potentially why these proteins mislocalize into the cytoplasm and may result in the disease (Lee, 2011).
Session chair, Magrane, reported on his effort to understand mitochondrial changes in ALS mice containing mutations in SOD1 and TDP43 similar to those found in ALS patients. These longitudinal studies included examining sciatic nerve and other tissue samples at 15, 45? and 90 day intervals – before and during the course of the disease. Magrane’s analysis showed, using live-cell imaging, that retrograde defects in mitochondria transport down the nerve can be observed as early as 45 days, during the pre-symptomatic stage of the SOD1 mouse. He found defects in both antegrade and retrograde movement of mitochondria when he examined the 90 day old tissue samples in the symptomatic stage of the SOD1 mouse. Magrane’s work also suggested that there was an abnormal level of mitochondria localizing at the neuromuscular junctions (NMJs) in the TDP43 mouse, in particular. Magrane here again used live-imaging, this time of synapses at the NMJ, to make this abnormal behavior apparent to the audience. His work suggests that since both mutant SOD1 and TDP43 models share mitochondrial abnormalities and dynamics that may represent a pathogenic “crossroad in motor neuron diseases,” such as ALS (Magrane, 2011).
Several other talks, not summarized here, were part of this session. For a full list of speakers, visit the Society for Neuroscience’s website by clicking here.
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Works Cited
Groen, E. (2011). Amyotrophic lateral sclerosis-associated mutations in FUS induce the redistribution of SMN1 to cytoplasmic inclusions and lead to changes in snRNA expression. 41st Annual Meeting (p. 15.02). Washington: Society for Neuroscience.
Lee, Y. (2011). Cytoplasmic mislocalization of TDP-43 and Fus. 41 Annual Meeting (p. 15.07). Washington: Society for Neurscience.
Magrane, J. (2011). Live imaging of mitochondrial dynamics in mouse models of amyotrophic lateral sclerosis. 41st Annual Meeting (p. 15.08). Washington: Society for Neuroscience.
Stankiewicz, T. (2011). Selective inhibition of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, induces neuronal cell death via a mechanism distinct from the Rho family GTPase inhibitor Toxin B. 41 Annual Meeting (p. 15.01). Washington: Society for Neuroscience.