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.
"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) "
[Show abstract][Hide abstract] 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.
Advances in genetics 09/2015; 91:1-53. DOI:10.1016/bs.adgen.2015.07.001 · 6.76 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.
Progress in Neurobiology 04/2014; 118. DOI:10.1016/j.pneurobio.2014.03.001 · 9.99 Impact Factor
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