Calcium Channel Agonists Protect against Neuromuscular Dysfunction in a Genetic Model of TDP-43 Mutation in ALS

Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, QC, H3C 3J7, Canada.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2013; 33(4):1741-52. DOI: 10.1523/JNEUROSCI.4003-12.2013
Source: PubMed


TAR DNA binding protein (TDP-43, encoded by the TARDBP gene) has recently been shown to be associated with amyotrophic lateral sclerosis (ALS), but the early pathophysiological deficits causing impairment in motor function are unknown. Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS.

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    • "The substitution with this novel cysteine residue causes the appearance of a prominent dimer due to the formation of an extra disulphide bond, following peroxide-induced oxidation. Armstrong and Drapeau (2013), Audet, Soucy, and Julien (2012), Cohen et al. (2011), Dewey et al. (2011), Kabashi et al. (2010), Schmid et al. (2013), Swarup, Audet, Phaneuf, Kriz, and Julien (2012), Swarup, Phaneuf, Bareil, et al. (2011), Swarup, Phaneuf, Dupre, et al. (2011), Tran et al. (2014); Voigt et al. (2010), Watanabe et al. (2013) "
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    ABSTRACT: At present, there are very few therapeutic options for patients affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, almost all patients affected by ALS or tau-negative FTD share in their brains the presence of aggregated TDP-43, a nuclear factor that plays an important role in regulating RNA metabolism. For this reason, this protein represents a very promising target to develop novel therapeutic options. Over the years, these options have mostly involved the search for new effectors capable of reducing aberrant aggregation or enhancing its clearance by UPS-dependent protein quality control or autophagy system. Targeting eventual mutations in the sequence of this protein might represent a parallel alternative therapeutic option. To this date, the study of various patient populations has allowed to find more than 50 mutations associated with disease. It is, therefore, important to better understand what the functional consequences of these mutations are. As discussed in this review, the emerging picture is that most TDP-43 mutations appear to directly relate to specific disease features such as increased aggregation, half-life, or altered cellular localization and protein-protein interactions.
    Full-text · Article · Sep 2015 · Advances in genetics
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    • "Interestingly, increased NMJ denervation (possibly due to dieback) has also been reported in rat and mouse models of TDP-43 mutations (Swarup et al., 2011; Zhou et al., 2010). In a follow-up study, expression of TARDBPG348C mRNA in zebrafish resulted in impaired neuromuscular synaptic transmission, reduced frequency of miniature endplate currents (mEPCs), reduced quantal transmission, orphaned presynaptic and postsynaptic structures at the NMJ, and motor neuron death following exposure to the glutamatergic agonist N-methyl-D-aspartate (NMDA) (Armstrong and Drapeau, 2013a). "
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    Full-text · Article · Jul 2014 · Disease Models and Mechanisms
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    • "Pharmacologically enhanced calcium entry with calcium channel agonists prevents the NMJ phenotype induced by an ALS human TARDBP mutation in zebrafish larvae (Armstrong and Drapeau, 2013b). A few other zebrafish genes have been investigated for the contribution of their loss of function in ALS-related symptoms. "
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