Article

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

ABSTRACT

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.

Full-text preview

Available from: jbc.org
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    No preview · Chapter · Dec 2015
  • Source
    • "Lipocalin-2 is a feature of inflammatory astrocytes (Zamanian et al., 2012) and can enhance reactive astrogliosis via autocrine signaling (Lee et al., 2009). Specific knockout of TDP-43 in cortical and MNs in mice produced a less severe phenotype, which further highlights the contribution of multiple cell types in ALS and FTD (Wu et al., 2012b; Iguchi et al., 2013). Interestingly, overexpression of ALS associated mutant TDP-43 driven by an astrocytic promoter was sufficient to cause MN degeneration in rats and was also associated with marked up-regulation of lipocalin-2 in reactive astrocytes (Tong et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.
    Full-text · Article · Oct 2015 · Frontiers in Cellular Neuroscience
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2014 · PLoS ONE
Show more