Familial ALS patients with TDP-43 gene mutations and sporadic ALS patients share common TDP-43 neuronal pathology. To delineate mechanisms underlying TDP-43 proteinopathies, transgenic mice expressing A315T, M337V or wild type human TDP-43 were generated. Multiple TDP-43 founders developed a severe early motor phenotype that correlated with TDP-43 levels in spinal cord. Three A315T TDP-43 lines developed later onset paralysis with cytoplasmic ubiquitin inclusions, gliosis and TDP-43 redistribution and fragmentation. The WT TDP-43 mouse line with highest spinal cord expression levels remains asymptomatic, although these mice show spinal cord pathology. One WT TDP-43 line with high skeletal muscle levels of TDP-43 developed a severe progressive myopathy. Over-expression of TDP-43 in vivo is sufficient to produce progressive motor phenotypes by a toxic gain of function paradigm. Transgenic mouse lines expressing untagged mutant and wild type TDP-43 under the same promoter represent a powerful new model system for studying TDP-43 proteinopathies in vivo.
"The cleavage of TDP-43 into a variety of detergent-insoluble, urea soluble fragments ranging from 17–35 kDa is a hallmark of FTLD-TDP and these fragments are a potential source of neuronal toxicity , , . Transgenic mice expressing wild type or familial ALS-linked mutant TDP-43 are characterized by the presence of 35 kDa and 25 kDa TDP-43 immunoreactive species , , , , , , , . However, the nature of these species is largely unknown. "
[Show abstract][Hide abstract] 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
"In agreement, histological examination of skeletal muscle from line 61 obese mice revealed normal muscle, indistinguishable from that of non-transgenics (Figure 2G). Skeletal muscle pathology in line 23, which develops weakness, shows denervation and atrophy as previously published . Thus, levels of TDP-43 expression in line 23 and line 61 mice are elevated in white adipose tissue, spinal cord, and skeletal muscle compared to non-transgenic mice. "
[Show abstract][Hide abstract] ABSTRACT: The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.
PLoS ONE 08/2013; 8(8):e71793. DOI:10.1371/journal.pone.0071793 · 3.23 Impact Factor
"Although some studies report on increased toxicity in mutant as compared to WT transgenic lines [9, 180, 222], other studies do not report such differences [177, 212, 213]. As the toxic effects of TDP-43 are clearly dose-dependent [177, 208, 213], some of these results may be dependent on the level of expression rather than on TDP-43 mutation-specific toxic effects. Furthermore, while it has been reported that TDP-43 WT overexpression has motor neuron-specific toxic effects coinciding with the presence of nuclear and cytoplasmic inclusions and pathological phosphorylation and cleavage of TDP-43 [89, 208, 213], overexpression of TDP-43 can be toxic without aggregate formation [9, 205]. "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.
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