Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

Institute of Molecular Biology, Academia Sinica, Taipei 11574, Taiwan.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2012; 287(33):27335-44. DOI: 10.1074/jbc.M112.359000
Source: PubMed


ALS, or amyotrophic lateral sclerosis, is a progressive and fatal motor neuron disease with no effective medicine. Importantly,
the majority of the ALS cases are with TDP-43 proteinopathies characterized with TDP-43-positive, ubiquitin-positive inclusions
(UBIs) in the cytosol. However, the role of the mismetabolism of TDP-43 in the pathogenesis of ALS with TDP-43 proteinopathies
is unclear. Using the conditional mouse gene targeting approach, we show that mice with inactivation of the Tardbp gene in the spinal cord motor neurons (HB9:Cre-Tardbplx/−) exhibit progressive and male-dominant development of ALS-related phenotypes including kyphosis, motor dysfunctions, muscle
weakness/atrophy, motor neuron loss, and astrocytosis in the spinal cord. Significantly, ubiquitinated proteins accumulate
in the TDP-43-depleted motor neurons of the spinal cords of HB9:Cre–Tardbplx/− mice with the ALS phenotypes. This study not only establishes an important role of TDP-43 in the long term survival and functioning
of the mammalian spinal cord motor neurons, but also establishes that loss of TDP-43 function could be one major cause for
neurodegeneration in ALS with TDP-43 proteinopathies.

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    • "In some cases (those related to a loss-of-function of the mutated protein, e.g., TDP- 43), knockout models have been also developed for the study of motor neuron injury (Wu et al., 2012). As mentioned above, these models have facilitated studies addressed to identify the key events in ALS pathogenesis that are more directly related to the specific gene used for modeling, but they have also served for evaluating numerous neuroprotective compounds or other disease-modifying strategies. "
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    ABSTRACT: Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the CNS and also in the periphery. One of these properties is the improvement of neuronal homeostasis and survival, which is exerted by the combination of beneficial effects on multiple targeted cytotoxic mechanisms. This potential is promising for acute and chronic neurodegenerative disorders, which are lacking at present of efficacious disease-modifying therapies. In this chapter, we review the experimental evidence supporting that different cannabinoid compounds may be neuroprotective in amyotrophic lateral sclerosis (ALS), a devastating chronic progressive neurodegenerative disorder affecting upper and/or lower motor neurons, which results in muscle denervation, atrophy, and paralysis. This experimental evidence supports a prompt and promising clinical exploitation of cannabinoid-based medicines for ALS and other motor neuron disorders.
    Cannabinoids in Neurologic and Mental Disease, 12/2015: pages 99-123; , ISBN: 9780124170414
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    • "These findings, coupled with the observation that many TDP-43 mutations occur around the prion-like motif, suggest that ALS and FTLD-TDP may be caused by aggregation of TDP-43 which inhibits its normal cellular activities. This loss of TDP-43 function may ultimately be instrumental in disease pathogenesis, and additionally the TDP-43 aggregates may sequester other essential RNAs and proteins [15]. Furthermore, the tremendous variety of reported TDP-43 inclusions suggests distinct mechanisms that may result from the misregulation of disease-specific and potentially overlapping signaling pathways that ultimately lead to TDP-43 accumulation and the subsequent functional deficits characteristic of all diseases with TDP-43 inclusions [16], [17]. "
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    ABSTRACT: Trans-activation Response DNA-binding Protein-43 (TDP-43) lesions are observed in Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration with ubiquitin inclusions (FTLD-TDP) and 25-50% of Alzheimer's Disease (AD) cases. These abnormal protein inclusions are composed of either amorphous TDP-43 aggregates or highly ordered filaments. The filamentous TDP-43 accumulations typically contain clean 10-12 nm filaments though wider 18-20 nm coated filaments may be observed. The TDP-43 present within these lesions is phosphorylated, truncated and ubiquitinated, and these modifications appear to be abnormal as they are linked to both a cellular heat shock response and microglial activation. The mechanisms associated with this abnormal TDP-43 accumulation are believed to result in a loss of TDP-43 function, perhaps due to the post-translational modifications or resulting from physical sequestration of the TDP-43. The formation of TDP-43 inclusions involves cellular translocation and conversion of TDP-43 into fibrillogenic forms, but the ability of these accumulations to sequester normal TDP-43 and propagate this behavior between neurons pathologically is mostly inferred. The lack of methodology to produce soluble full length TDP-43 and recapitulate this polymerization into filaments as observed in disease has limited our understanding of these pathogenic cascades. The protocols described here generate soluble, full-length and untagged TDP-43 allowing for a direct assessment of the impact of various posttranslational modifications on TDP-43 function. We demonstrate that Casein Kinase II (CKII) promotes the polymerization of this soluble TDP-43 into 10 nm diameter filaments that resemble the most common TDP-43 structures observed in disease. Furthermore, these filaments are recognized as abnormal by Heat Shock Proteins (HSPs) which can inhibit TDP-43 polymerization or directly promote TDP-43 filament depolymerization. These findings demonstrate CKII induces polymerization of soluble TDP-43 into filaments and Hsp90 promotes TDP-43 filament depolymerization. These findings provide rational for potential therapeutic intervention at these points in TDP-43 proteinopathies.
    PLoS ONE 03/2014; 9(3):e90452. DOI:10.1371/journal.pone.0090452 · 3.23 Impact Factor
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    • "Loss of TDP-43 also appears to be deleterious to cell health; knockdown in vitro confers toxicity and knockout results in lethality in vivo, both in utero in constitutive Tardbp−/− mice and in conditional knockout animals in which deletion is postponed until adulthood [13], [14], [15], [16]. Loss of TDP-43 specifically in motor neurons results in cell death and an ALS-like phenotype in mice [17] and reduced TDP-43 expression in zebrafish and drosophila results in motor deficits [18], [19]. "
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    ABSTRACT: The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy.
    PLoS ONE 01/2014; 9(1):e86513. DOI:10.1371/journal.pone.0086513 · 3.23 Impact Factor
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